Pharmaceutical formulations comprising paclitaxel, derivatives, and pharmaceutically acceptable salts thereof

ABSTRACT

The invention concerns paclitaxel solubilizers and formulations thereof with a high propensity to dissolve paclitaxel. The formulations of the invention reduce or obviate the need for the disadvantageous excipient Cremophor® EL. The formulations of the invention are useful for administering paclitaxel, its derivatives, or pharmaceutically acceptable salts or such derivatives to patients in need thereof. The formulations of the invention are suitable for parenteral, oral, local, or transdermal administration to mammals including humans, particularly for intravenous delivery.

[0001] This application claims the benefit of U.S. ProvisionalApplication No. 60/253,640 filed Nov. 28, 2000, and U.S. ProvisionalApplication No. 60/272,117 filed Feb. 28, 2001, which are incorporatedby reference herein in their entirety.

1. FIELD OF THE INVENTION

[0002] The present invention is directed to excipients or combinationsthereof suitable for preparing a formulation containing a pharmaceuticalagent. More particularly, the invention is directed to stable andefficacious pharmaceutical formulations comprising paclitaxel,derivatives, and pharmaceutically acceptable salts thereof.

2. BACKGROUND OF THE INVENTION

[0003] Pharmaceuticals are rarely distributed as pure compounds becauseof problems with, among others, stability, solubility, andbioavailability of the pharmaceutical itself (i.e., the active), and inmost cases, are administered in a pharmaceutical formulation comprisingthe active, and other components, such as excipients, binders, diluents,and other delivery vehicles or systems. It is well documented thatphysical and chemical properties, such as stability, solubility,dissolution, permeability, and partitioning of most pharmaceuticals aredirectly related to the medium in which they are administered. And, inturn, the physical and chemical properties of drug-in-formulationmixtures affect the pharmacological and pharmacokinetic properties, suchas absorption, bioavailability, metabolic profile, toxicity, andpotency. Such effects are caused by interactions between theformulation's components and the pharmaceutical and/or interactionsbetween the components themselves. Other properties influenced by theformulation in which a pharmaceutical is administered include mechanicalproperties, such as compressibility, compactability, and flowcharacteristics and sensory properties, such as taste, smell, and color.Thus, discovery of pharmaceutical formulations that optimizebioavailability and duration of action of the pharmaceutical andminimize undesirable properties is an important part of pharmaceuticaldevelopment and research. For a general review of the subject offormulations see Howard, Introduction to Pharmaceutical Dosage Forms,Lea & Febiger, Philadelphia Pa., 4^(th) ed., 1985; Remington: theScience and Practice of Pharmacy, Alfonso R. Gennaro ed., MackPublishing Co. Easton, Pa., 19th ed., 1995, Chapter 83.

[0004] Formulation development is normally a tedious process, where manyvariables must be separately assessed. For example, if the formulationcontains a pharmaceutical characterized by poor solubility, thesolubility of the pharmaceutical in a range of salt concentrations; pHs;excipients; and pharmaceutical concentrations must be prepared andtested to find interactions between the pharmaceutical and excipients orinteractions between excipients that affect the pharmaceutical'ssolubility. While some general rules exist, the effect of excipients andcombinations of excipients on the physical and chemical properties ofthe pharmaceutical are not easily predicted. Moreover, there are over3,000 excipients to choose from when designing pharmaceuticalformulations, each having differing degrees and types of interactionswith each other and with the pharmaceutical. (For a listing of generallyregarded as safe (GRAS) excipients see the Code of Federal Regulations(CFR) at 21 CFR 182 and 21 CFR 184). Because of the many variablesinvolved, industry does not have the time or resources to identify,measure, or exploit interactions between excipients and pharmaceuticalsand thus cannot provide optimized pharmaceutical formulations tailoredto the particular pharmaceutical. Such work would require testinghundreds to thousands of formulations a day. Assuming three hundredsubstances are to be tested for efficacy as excipients in apharmaceutical formulation, even with no variations in concentrationsand no physical or chemical property variations, the number of possiblecombinations is enormous: when two of the substances are selected, thereare 45,150 possible combinations, for three components there are4,545,100 combinations, and for four components, there are 344,291,325possible combinations. The complexity is increased when the relativeratio of each component is considered. Unfortunately, technologies thatcan make many pharmaceutical-excipient combinations at the same time,then automatically feed each combination into a system for identifyingthe combinations that have optimized properties are not known. Today,since it is more cost effective, most pharmaceuticals are distributedand administered in the standard, un-optimized formulations, see e.g.,Allen 's Compounded Formulations: U.S. Pharmacists Collection 1995 to1998, ed. Lloyd Allen.

[0005] Paclitaxel is presently available in the United States only as anon-aqueous sub-optimal formulation concentrate for intravenousinjection. An intravenous dosage regimen of 135 mg/m² paclitaxel isrecommended for previously untreated patients with carcinoma of theovary, given every three weeks. Similar dosage regimens are recommendfor other carcinomas. Paclitaxel is practically insoluble in water. Thecommercially-available paclitaxel formulation (Bristol-Myers Squibb)comprises 6 mg/ml of paclitaxel dissolved in Cremophor® EL (PEG-35castor oil, polyoxyethylated castor oil) and dehydrated ethanol (50%v/v). Similar formulations are sold by other manufacturers, for example,IVAX Co. Before intravenous injection, the commercial dose must bediluted to a final concentration of 0.3 to 1.2 mg/ml prior to injection.Recommended diluents are 0.9% aqueous sodium chloride, 5% aqueousdextrose, or 0.9% sodium chloride 5% dextrose aqueous solution, or 5%dextrose in Ringer's injection (The Physician's Desk Reference, 54thedition, 881-887,Medical Economics Company (2000); Goldspiel 1994 Ann.Pharmacotherapy 28:S23-26, both of which are incorporated herein byreference).

[0006] In general, the amount of Cremophor® EL necessary to deliver therequired doses of paclitaxel is significantly higher than thatadministered with other drugs currently formulated in Cremophor® EL.This is a particular problem since several toxic effects have beenattributed to Cremophor® EL, including vasodilation, dyspnea, andhypotension. This vehicle has also been shown to cause serioushypersensitivity in laboratory animals and humans (Weiss et al., 1990,J. Clin. Oncol. 8:1263-1268). In fact, the maximum dose of paclitaxelthat can be administered to mice by i.v. bolus injection is dictated bythe acute lethal toxicity of the Cremophor® EL vehicle (Eiseman et al.,1994, Cancer Chemother. Pharmacol. 34:465-471).

[0007] In addition, Cremophor® EL is known to leach phthalateplasticizers such as di(2-ethylhexyl)phthalate (DEHP) from thepolyvinylchloride bags and intravenous administration tubing. DEHP isknown to cause hepatotoxicity in animals and is carcinogenic in rodents.Upon dilution with infusion solutions, paclitaxel Cremophor® ELformulations can result in particulate formation. In addition, fibrousprecipitates of unknown composition can form in the concentrate duringstorage for extended periods of time. It is generally believed that theprecipitates are degradation by-products of either components in thesolvent or paclitaxel. In such case, filtration of the dilutedCremophor® EL/ethanol/paclitaxel formulation is necessary duringadministration (Goldspiel 1994 Ann. Pharmacotherapy 28:S23-26).

[0008] It has further been reported, in U.S. Pat. No. 5,504,102, thatcommercial grade Cremophor® EL with ethanol as a co-solvent, althougheffective in dissolving paclitaxel, produces injection formulations thatexhibit instability over extended periods of time. In particular,pharmaceutical formulations of paclitaxel in a co-solvent of 50:50 byvolume of dehydrated ethyl alcohol and commercial grade Cremophor® ELexhibit a loss of potency of greater than 60% after storage for 12 weeksat 50° C. The loss of potency is attributed to the degradation ofpaclitaxel during storage. Other disadvantages of. Cremophor® EL havebeen reported.

[0009] Some efforts have focused on limiting or eliminating Cremophor®EL by preparing paclitaxel derivatives having improved aqueoussolubility over paclitaxel. Research in this area includes preparationof 2′-succinate- and amino-acid-ester prodrugs of paclitaxel (see e.g.,Deutsch et al., 1989, J. Med. Chem., 32:788-792; Matthew et al., 1992,J. Med. Chem. 35:145-151). In other efforts, Greenwald et al. reportedthe synthesis of highly water-soluble 2′ and 7-polyethylene glycolesters of paclitaxel (Greenwald et al., 1994, Bioorganic & MedicinalChemistry Letters 4:2465-2470), however, no data concerning the in-vivoantitumor activity of these compounds were reported (Greenwald et al.,1995, J. Org. Chem. 60:331-336). Others attempts to solve paclitaxel'saqueous-solubility problems have involved microencapsulation ofpaclitaxel in both liposomes and nanospheres (Bartoni et al., 1990, J.Microencapsulation 7:191-197). The liposome formulation was reported tobe as effective as free paclitaxel, however, only liposome formulationscontaining less than 2% paclitaxel were physically stable (Sharma etal., 1994, Pharm. Res. 11:889-896). There is a need, therefore, forformulations comprising paclitaxel, derivatives, and pharmaceuticallyacceptable salts thereof that can deliver therapeutically effectiveamounts of paclitaxel and derivatives thereof that overcome thedisadvantages caused by paclitaxel's insolubility and the disadvantagesof Cremophor® EL.

3. SUMMARY OF THE INVENTION

[0010] In a preferred embodiment, the invention concerns paclitaxelsolubilizers and formulations thereof with a high propensity to promotedissolution of paclitaxel or that stabilize aqueous paclitaxelsolutions. The formulations of the invention are useful foradministering paclitaxel, its derivatives, or pharmaceuticallyacceptable salts of such derivatives to patients in need thereof. Theformulations of the invention are suitable for parenteral, oral, local,or transdermal administration to mammals including humans, particularlyfor intravenous delivery.

[0011] More generally, the paclitaxel solubilizers of the invention ormixtures thereof can replace the disadvantageous excipient Cremophor® ELas a solubilizing excipient in existing pharmaceutical formulationscomprising hydrophobic pharmaceuticals or the need to use Cremophor® ELwith such pharmaceuticals. Thus, the formulations of the invention aresuitable to administer any drug for which Cremophor® EL is now used orwould today be the first choice as an aqueous solubilization excipient.The formulations of the invention are particularly suitable toadminister paclitaxel and derivatives thereof.

[0012] In one embodiment, the invention concerns a pharmaceuticalformulation for administration to a mammal comprising:

[0013] (a) paclitaxel, a derivative, or a pharmaceutically acceptablesalt thereof; and

[0014] (b) one or more of a PEG-glyceryl fatty ester, a quaternaryammonium salt or a PEG-fatty alcohol.

[0015] In this embodiment, preferably, the quaternary ammonium salt isbenzalkonium chloride, benzethonium chloride, or cetrimide; thePEG-glyceryl fatty ester is PEG-glyceryl monooleate or PEG-glycerylmonolaurate; and the PEG-fatty alcohol is an octoxynol, an oleth, or alaureth.

[0016] In another embodiment, the invention concerns a pharmaceuticalformulation for administration to a mammal comprising:

[0017] (a) paclitaxel, a derivative, or a pharmaceutically acceptablesalt thereof; and

[0018] (b) two or more of a PEG-vitamin E, a quaternary ammonium salt, aPEG-monoacid fatty ester, a PEG-glyceryl fatty ester, a polysorbate, ora PEG-fatty alcohol.

[0019] Preferably, the PEG-vitamin E is tocophersolan; the quaternaryammonium salt is benzalkonium chloride, benzethonium chloride, orcetrimide; the PEG-monoacid fatty ester is PEG-20 monooleate, PEG-20monolaurate, PEG-20 monostearate; the PEG-glyceryl fatty ester is PEG-20glyceryl monooleate, PEG-20 glyceryl monostearate, or PEG-20 glycerylmonolaurate; the polysorbate is polysorbate 20 or polysorbate 80; andthe PEG-fatty alcohol is an octoxynol, an oleth, or a laureth. Apreferred octoxynol is octoxynol-9 and preferred laureth is laureth-23.

[0020] In a separate embodiment, the formulations of the invention donot contain a quaternary ammonium salt.

[0021] In one preferred aspect of this embodiment, the paclitaxelsolubilizers are a PEG-vitamin E and one or more of a PEG-monoacid fattyester, the PEG-glyceryl fatty ester, a polysorbate, or a PEG-fattyalcohol.

[0022] In another preferred aspect of this embodiment, the paclitaxelsolubilizers are a quaternary ammonium salt and one or both of apolysorbate or a PEG-fatty alcohol.

[0023] In still another preferred aspect of this embodiment, thepaclitaxel solubilizers are a PEG-monoacid fatty ester and one or moreof a PEG-vitamin E, the PEG-glyceryl fatty ester, a polysorbate, or aPEG-fatty alcohol.

[0024] In another embodiment, the paclitaxel solubilizers are aPEG-glyceryl fatty ester and one or more of the PEG-vitamin E, thePEG-monoacid fatty ester, or the polysorbate.

[0025] In yet another preferred aspect of this embodiment, thepaclitaxel solubilizers are a polysorbate and one or more of aquaternary ammonium salt, a PEG-monoacid fatty ester, a PEG-glycerylfatty ester, or a PEG-fatty alcohol.

[0026] In another preferred aspect of this embodiment, the paclitaxelsolubilizers are a PEG-fatty alcohol and one or more of a PEG-vitamin E,a quaternary ammonium salt, a PEG-monoacid fatty ester, or apolysorbate.

[0027] In another embodiment, the invention concerns a pharmaceuticalformulation for administration to a mammal comprising:

[0028] (a) paclitaxel, a derivative, or a pharmaceutically acceptablesalt thereof; and

[0029] (b) PEG-400 and one or more of a PEG-vitamin E, a quaternaryammonium salt, a PEG-monoacid fatty ester, a PEG-glyceryl fatty ester, apolysorbate, or a PEG-fatty alcohol.

[0030] In a separate embodiment, the invention relates to a method oftreating cancer or other conditions treatable by paclitaxel in a mammalcomprising administering to said mammal a therapeutically effectiveamount of a formulation of the invention.

[0031] In still another embodiment, the formulations of the inventioncan be independent of paclitaxel, a derivative, or a salt thereof. Suchformulations are referred to herein as paclitaxel free formulations ofthe invention and can be used to solubilize and administer anypharmaceutical. Paclitaxel free formulations of the invention areparticularly useful as a replacement for cremophor and similarexcipients in pharmaceutical formulations currently comprising them.

[0032] In another embodiment, the invention relates to a pharmaceuticalformulation suitable for administration to a human consistingessentially of:

[0033] (a) paclitaxel, a derivative, or a pharmaceutically acceptablesalt thereof;

[0034] (b) one or more of a PEG-vitamin E, a quaternary ammonium salt, aPEG-monoacid fatty ester, a PEG-glyceryl fatty ester, a polysorbate, ora PEG-fatty alcohol; and

[0035] (c) ethanol,

[0036] wherein said formulation is free of cremophor and is suitable fordissolution or reconstitution with an aqueous medium into aparticulate-free solution suitable for parenteral administration.

[0037] In yet another embodiment, the invention relates to apharmaceutical formulation suitable for administration to a humanconsisting essentially of:

[0038] (a) paclitaxel, a derivative, or a pharmaceutically acceptablesalt thereof;

[0039] (b) two or more of a PEG-vitamin E, a quaternary ammonium salt, aPEG-monoacid fatty ester, a PEG-glyceryl fatty ester, a polysorbate, ora PEG-fatty alcohol; and

[0040] (c) ethanol,

[0041] wherein said formulation is free of cremophor and is suitable fordissolution or reconstitution with an aqueous medium into aparticulate-free solution suitable for parenteral administration.

[0042] In another embodiment, the invention relates to arrays andmethods for high-throughput preparation of a large number ofexcipient/active combinations (e.g., thousands to hundreds ofthousands), at varying concentrations, at the same time, andhigh-throughput testing thereof. An example of such a process isdescribed in the Examples section herein. Such methods allow detectionor measurement of interactions between formulation components (e.g.,excipients) and actives; between multiple formulation components; orbetween multiple actives. Once such interactions or lack of interactionsare identified, the active can be “retrofitted” into an optimalformulation for pharmaceutical administration.

[0043] The invention thus encompasses the high-throughput testing offormulations comprising paclitaxel, a derivative, or a salt thereof inorder to determine the overall optimal formulations, or to optimize anyparticular desired property or results, e.g., bioavailability, potency,release, stability, and the like; or both. To applicant's knowledge, asystematic, high-throughput method for formulation generation,screening, testing, and analysis, has not been published prior to thisinvention.

[0044] In this regard, another embodiment of the invention concerns anarray of samples, each sample comprising paclitaxel, a derivative, or apharmaceutically acceptable salt thereof and at least one formulationcomponent, wherein each sample differs from any other sample withrespect to at least one of:

[0045] (i) the identity of the formulation component, or

[0046] (ii) the ratio of the paclitaxel, the derivative, or thepharmaceutically acceptable salt thereof to the formulation component.

[0047] In still another embodiment, the invention relates to a method tofind a pharmaceutical formulation suitable to administer paclitaxel tomammal, comprising:

[0048] (a) preparing an array of samples, each sample comprisingpaclitaxel, a derivative, or a pharmaceutically acceptable salt thereofand a formulation component, wherein each sample differs from any othersample with respect to at least one of:

[0049] (i) the identity of the formulation component,

[0050] (ii) the ratio of the paclitaxel, the derivative, or thepharmaceutically acceptable salt thereof to the formulation component;and

[0051] (b) testing each sample for a property.

[0052] In still another embodiment, the invention relates to aparticulate-free pharmaceutical formulation suitable for parenteraladministration to a mammal comprising about 0.2 mg/ml to about 3.0 mg/mlof paclitaxel in a non-cremophor aqueous-based solution, where per mg ofthe paclitaxel in the formulation the amount of water is about 4.5 ml toabout 0.3 ml.

3.1 BRIEF DESCRIPTION OF THE DRAWINGS

[0053]FIG. 1 is a pK profile comparison of 1) commercially availableTAXOL® (Bristol-Myers Squibb Company), 2) Formulation V, and 3)Formulation W, in each case, upon adminstration of a 5 mg/kg bolus dosein male Sprague-Dawley rats.

[0054]FIG. 2 is a pK profile comparison of 1) commercially availableTAXOL®2) Formulation V, and 3) Formulation W, in each case, uponadminstration of a 10 mg/kg bolus dose in male Sprague-Dawley rats.

[0055]FIG. 3 is a pK profile comparison of 1) Formulation V uponadminstration of a 5 mg/kg bolus dose, and 2) Formulation V uponadminstration of a 10 mg/kg bolus dose, in male Sprague-Dawley rats.

[0056]FIG. 4 is a pK profile comparison of 1) Formulation W uponadminstration of a 5 mg/kg bolus dose, and 2) Formulation W uponadminstration of a 10 mg/kg bolus dose, in male Sprague-Dawley

3.2 DEFINITIONS

[0057] The term “mammal” as used herein, encompasses any mammal.Preferably a mammal is in need of a formulation of the invention.Examples of mammals include, but are not limited to, cows, horses,sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys,etc., more preferably, a human.

[0058] As referred to herein, derivatives and analogs of paclitaxelinclude, but are not limited to, docetaxel and compounds having thegeneral formula I below and stercoisomers and pharmaceuticallyacceptable salts thereof:

[0059] wherein, each occurrence of R is independently H, (C₁-C₆)alkyl,aryl, C(O)(C₁-C₆)alkyl, or C(O)aryl. Preferably, (C₁-C₆)alkyl is methyland aryl is phenyl. Such derivatives are well known in the art. Forexample, paclitaxel derivatives encompassed by formula I are disclosedin U.S. Pat. Nos. 5,399,726; 5,654,447; 6,066,747; 5,338,872; 6,107,332;5,703,117; 5,714,512; 5,580,899; 6,118,011; 5,470,866; 5,319,112; and6,136,961.

[0060] As used herein, “paclitaxel solubilizer” means one or a mixtureof substances that has a high propensity to solubilize paclitaxel in anaqueous medium. Preferably, a paclitaxel solubilizer, when included inan aqueous paclitaxel medium, can dissolve the paclitaxel at roomtemperature to a concentration of at least about 1.2 mg/ml water. A“paclitaxel solubilizer of the invention” refers to PEG-Vitamin Es,quaternary ammonium salts, PEG-monoacid fatty esters, polysorbates, andPEG-fatty alcohols or combinations thereof. It is to be understood thata “paclitaxel solubilizer” can be used to solubilize, distribute, andadminister drugs generally, for example, the paclitaxel solubilizers ofthe invention can be used to solubilize, distribute, and administer, butnot limited to, other cancer and cancer-related pharmaceuticals, such ascisplatin, carboplatin, epirubicin, leuprolide, bicalutamide, goserelinimplant, irinotecan, gemcitabine, and sargramostim; cardiovasculardrugs; such as amlodipine besylate, enalapril maleate, losartanpotassium lisinopril, irbesartan, nifedipine, diltiazem, clopidogrel,digoxin, abciximab, furosemide, amiodarone, beraprost, and tocopheryl;anti-infective agents, such as amoxicillin, clavulanate, ciprofloxacin,azithromycin, itraconazole, acyclovir fluconazole, terbinafine,erythromycin, and sulfisoxazole acetyl; psychotherapeutic agents, suchas fluoxetine, paroxetine, sertaline, vanlafaxine, bupropion,olanzapine, alprazolam, methylphenidate, fluvoxamine, and ergoloid;gastrointestinal medicaments, such as omeprazole, lansoprazole,ranitidine, famotidine, ondansetron, granisetron, sulfasalazine, andinfliximab; respiratory therapies, such as loratadine, fexofenadine,cetirizine, fluticasone, salmeterol xinafoate, and budesonide;cholesterol reducers, such as simvastatin, atorvastatin calcium,pravastatin, lovastatin, bezafibrate, ciprofibrate, and gemfibrozil;blood modifiers, such as epoetin alpha, enoxaparin, and antihemophilicfactor; antiarthritic agents, such as celecoxib, diclofenac sodium,nabumetone, misoprostol, and rofecoxib; AIDS and AIDS-related drugs,such as lamivudine, zidovudine, indinavir, stavudine, and lamivudine;diabetes and diabetes-related therapies, such as metformin,troglitazone, and acarbose; biologicals, such as hepatitis vaccines;Hormones, such as estradiol; immunosuppressive agents, such ascyclosporine, mycophenolate mofetil, and methylprednisolone; analgesics,such as tramadol, fentanyl, metamizole, ketoprofen, morphine, lysineacetylsalicylate, ketoralac tromethamine, morphine, loxoprofen sodium,and ibuprofen; dermatological products, such as isotretinoin andclindamycin; anesthetics, such as propofol, midazolam, and lidocaine;migraine therapies, such as sumatriptan succinate, zolmitriptan, andrizatriptan; sedatives and hypnotics, such as, zolpidem, triazolam, andhycosine butylbromide; multiple sclerosis agents, such as interferonbeta-1a, interferon beta-1a, and glatiramer; osteoporosis agents, suchas vitamin k₂; cystic fibrosis agents, such as dornase alpha andtobramycin; Alzheimer's disease therapies, such as dolasetron anddonepezil; and imaging agents, such as iohexol, technetium Tc99msestamibi, iomeprol, gadodiamide, ioversol, and ioprornide; orpharmaceutically acceptable salts thereof.

[0061] The term “active” refers to a pharmaceutical, more specificallyto paclitaxel, derivatives, and pharmaceutically acceptable saltsthereof.

[0062] The term “cremophor” means PEG-35 caster oil (commerciallyavailable from BASF, Washington, NJ, under the trade name Cremophor®EL).

[0063] As used herein, the phrase “formulations of the invention” refersto a specific composition or combination of ingredients (i.e., one ormore paclitaxel solubilizer(s) and any other excipients, diluents, orcarriers) useful for administering, delivering, or distributingpaclitaxel, a derivative, or salt thereof. A “formulations of theinvention” may or may not include an active. Preferably, theformulations of the invention are suitable for reconstitution ordissolution in an aqueous medium to a particulate-free, injectablesolution. It is also preferable that formulations of the invention aresterile. A formulation of the invention can be in the form of a solid,liquid, semisolid, gel, suspension, emulsion, or a solution. A solutionincludes both aqueous and organic solvent solutions and liquidconcentrates thereof.

[0064] As used herein, a “liquid concentrate” means a solution of activeand one or more paclitaxel solubilizers of the invention, preferably inan organic solvent, such as ethanol, that is to be diluted with anaqueous medium prior to administration. A liquid concentrate can includevarious amounts of water but is preferably substantially anhydrous.

[0065] Solids include any solid form, such as a powder, a compressedpharmaceutical dosage form, or a lyophilized solid. In one embodiment,formulations of the invention if solid or other than liquid, aresuitable for reconstitution into an injectable, particulate-free,preferably sterile formulation, such as an aqueous medium.

[0066] An “aqueous medium” will comprise at least water. Preferably, anaqueous medium is sterile and suitable for use as a carrier of an activefor administration to a mammal. Examples of preferred aqueous mediumsinclude, but are not limited to, water; saline solution; Ringer'ssolution; and solutions of water-miscible substance, such as dextroseand other electrolytes. Other aqueous mediums suitable for parenteraladministration of actives are listed in Remington: the Science andPractice of Pharmacy, Alfonso R. Gennaro ed., Mack Publishing Co.Easton, Pa., 19th ed., 1995, Chapter 87; incorporated herein byreference. Preferably, the aqueous medium does not affect the ability ofthe paclitaxel solubilizer of the invention to solubilize paclitaxel,derivatives, or salts thereof.

[0067] The phrase “pharmaceutically acceptable salt(s)”, as used herein,means those salts of paclitaxel derivatives that retain the biologicaleffectiveness and properties of the free acids or free bases and thatare not otherwise unacceptable for pharmaceutical use. Pharmaceuticallyacceptable salts of paclitaxel derivatives include salts of acidic orbasic groups which may be present in the paclitaxel derivatives.Derivatives of paclitaxel that are basic in nature are capable offorming a wide variety of salts with various inorganic and organicacids. The acids that may be used to prepare pharmaceutically acceptableacid addition salts of such basic compounds are those that formnon-toxic acid addition salts, i.e., salts containing pharmacologicallyacceptable anions, such as chloride, bromide, iodide, nitrate, sulfate,bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate,salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate,ascorbate, succinate, maleate, gentisinate, fumarate, gluconate,glucaronate; saccharate, formate, benzoate, glutamate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Derivatives ofpaclitaxel that include an amino moiety can also form pharmaceuticallyacceptable salts with various amino acids, in addition to the acidsmentioned above. Derivatives of paclitaxel that are acidic in nature arecapable of forming a wide variety of salts with various inorganic andorganic bases. Suitable base salts are formed from bases that donatecations to form non-toxic salts, suitable cations include, but are notlimited to, sodium, aluminum, calcium, lithium, magnesium, potassium,zinc and diethanolamine salts. For a review on pharmaceuticallyacceptable salts see Berge et al., J. Pharm. Sci., 66, 1-19 (1977),incorporated herein by reference.

[0068] As used herein, the term “excipient” means the substances used toformulate actives into pharmaceutical formulations; in a preferredembodiment, an excipient does not lower or interfere with the primarytherapeutic effect of the active. Preferably, an excipient istherapeutically inert. The term “excipient” encompasses carriers,diluents, vehicles, solubilizers, stabilizers, and binders. Excipientscan also be those substances present in a pharmaceutical formulation asan indirect result of the manufacturing process. Preferably, excipientsare approved for or considered to be safe for human and animaladministration, i.e., GRAS substances (generally regarded as safe). GRASsubstances are listed by the Food and Drug administration in the Code ofFederal Regulations (CFR) at 21 CFR 182 and 21 CFR 184, incorporatedherein by reference.

[0069] As used herein, the phrase “array” means a plurality of samplesassociated under a common experiment, wherein each of the samplescomprises at least paclitaxel, a derivative, or salt thereof (i.e., anactive) and a formulation component. The array is designed to provide adata set, analysis of which allows detection or measurement ofinteractions (including lack of interactions) between the active and theformulation component. Samples in the array differ from other samples inthe array with respect to at least one of:

[0070] (i) the identity of the formulation component, or

[0071] (ii) the ratio of the active to the formulation component.

[0072] According to the invention, the ratio of the active to theformulation component will differ between samples when such ratio isintentionally varied to induce a measurable change in the sample'sproperties.

[0073] As used herein, the term “property” means a physical or chemicalcharacteristic of a sample. Preferred properties are those that relateto the efficacy, safety, stability, or utility of formulations before orafter administration. Properties include physical properties, forexample, but not limited to, rheology, friability, stability,solubility, dissolution, and permeability, preferably, solubility. Theterm “property” also includes mechanical properties, for example, butnot limited to, compressibility, compactability, and flowcharacteristics.

[0074] An array can comprise 24, 36, 48, 96, or more samples, preferably1000 or more samples, more preferably, 10,000 or more samples. An arrayis typically comprises one or more sub-arrays. For example, a sub-arraycan be a 96-well plate of sample wells.

[0075] As used herein, the term “sample” means a mixture of paclitaxel,a derivative, or salt thereof (i.e., an active) and one or moreformulation components. The term “sample” encompasses duplicates,triplicates, etc. of the same sample used as controls in an array. Inother words, multiples of the same sample in an array, for controlpurposes, are considered one sample for the purposes of the invention.Preferably a sample comprises 2 or more formulation components, morepreferably, 3 or more formulation components. A sample can be present inany container or holder or in or on any material or surface, the onlyrequirement is that the samples be located at separate sites.Preferably, samples are contained in sample wells, for example, a 24,36, 48, or 96 well plates (or filter plates) of volume 250 ul availablefrom Millipore, Bedford, Mass.

[0076] As used herein, the phrase “formulation component” means anysubstance in addition to the active in a sample. Preferably, aformulation component is therapeutically inactive. Examples of suitableformulation components include, but are not limited to, excipients,solvents, diluents, stabilizers, and combinations thereof.

[0077] As used herein, the term “alkyl group” means a saturated,monovalent, unbranched or branched hydrocarbon chain. Examples of alkylgroups include, but are not limited to, (C₁-C₂₅)alkyl groups, such asmethyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl,2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl,2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl,4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl,4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl,2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl,hexyl, and longer alkyl groups, such as heptyl, and octyl, nonyl, decyl,undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl,heptadecyl, octadecyl, nonadecyl, icosanyl, heniconsanyl, docosanyl,tricosanyl, tetracosanyl, and pentacosanyl. An alkyl group can beunsubstituted or substituted with one or more suitable substituents.

[0078] An “alkenyl group” means a monovalent, unbranched or branchedhydrocarbon chain having one or more double bonds therein. The doublebond of an alkenyl group can be unconjugated or conjugated to anotherunsaturated group. Suitable alkenyl groups include, but are not limitedto (C₂-C₂₅)alkenyl groups, such as vinyl, allyl, butenyl, pentenyl,hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl,2-propyl-2-butenyl, 4-(2-methyl-3-butene)-pentenyl, nonenyl, decenyl,undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl,hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, icosanenyl,heniconsanenyl, docosanenyl, tricosanenyl, tetracosanenyl, andpentacosanenyl. An alkenyl group can be unsubstituted or substitutedwith one or more suitable substituents.

[0079] An “alkynyl group” means monovalent, unbranched or branchedhydrocarbon chain having one or more triple bonds therein. The triplebond of an alkynyl group can be unconjugated or conjugated to anotherunsaturated group. Suitable alkynyl groups include, but are not limitedto, (C₂-C₂₅)alkynyl groups, such as ethynyl, propynyl, butynyl,pentynyl, hexynyl, methylpropynyl, 4-methyl-1-butynyl,4-propyl-2-pentynyl, 4-butyl-2-hexynyl, nonynyl, decynyl, undecynyl,dodecynyl, tridecynyl, tetradecynyl, pentadecynyl, hexadecenyl,heptadecynyl, octadecynyl, nonadecynyl, icosanynyl, heniconsanynyl,docosanynyl, tricosanynyl, tetracosanynyl, and pentacosanynyl. Analkynyl group can be unsubstituted or substituted with one or moresuitable substituents.

[0080] An “aryl group” means a monocyclic or polycyclic-aromatic ringcomprising carbon and hydrogen atoms. Examples of suitable aryl groupsinclude, but are not limited to, phenyl, tolyl, anthacenyl, fluorenyl,indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclicmoieties such as 5,6,7,8-tetrahydronaphthyl. An aryl group can beunsubstituted or substituted with one or more suitable substituents.Preferably, the aryl group is a monocyclic ring, wherein the ringcomprises 6 carbon atoms, referred to herein as “(C₆)aryl”.

[0081] A “cycloalkyl group” means a monocyclic or polycyclic saturatedring comprising carbon and hydrogen atoms and having no carbon-carbonmultiple bonds. Examples of cycloalkyl groups include, but are notlimited to, (C₃-C₇)cycloalkyl groups, such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and cycloheptyl, and saturated cyclic andbicyclic terpenes. A cycloalkyl group can be unsubstituted orsubstituted by one or more suitable substituents. Preferably, thecycloalkyl group is a monocyclic ring or bicyclic ring.

[0082] The term “alkoxy group” means an —O-alkyl group, wherein alkyl isas defined above. An alkoxy group can be unsubstituted or substitutedwith one or more suitable substituents. Preferably, the alkyl chain ofan alkoxy group is from 1 to 25 carbon atoms in length, referred toherein as “(C₁-C₂₅)alkoxy”.

[0083] The term “aryloxy group” means an —O-aryl group, wherein aryl isas defined above. An aryloxy group can be unsubstituted or substitutedwith one or more suitable substituents. Preferably, the aryl ring of anaryloxy group is a monocyclic ring, wherein the ring comprises 6 carbonatoms, referred to herein as “(C₆)aryloxy”.

[0084] The term “benzyl” means —CH₂-phenyl.

[0085] The term “phenyl” means —C₆H₅. A phenyl group can beunsubstituted or substituted with one or more suitable substituents.

[0086] A “carbonyl” group is a divalent group of the formula —C(O)—.

[0087] An “alkoxycarbonyl” group means a monovalent group of the formula—C(O)-alkoxy. Preferably, the hydrocarbon chain of an alkoxycarbonylgroup is from 1 to 25 carbon atoms in length.

[0088] As used herein, “halogen” means fluorine, chlorine, bromine, oriodine. Correspondingly, the meaning of the terms “halo” and“Hal”encompass fluoro, chloro, bromo, and iodo.

[0089] As used herein, a “suitable substituent” means a group that doesnot nullify the synthetic or pharmaceutical utility of the active or thepaclitaxel solubilizer of the invention. Examples of suitablesubstituents include, but are not limited to: (C₁-C₈)alkyl;(C₁-C₈)alkenyl; (C₁-C₈)alkynyl; (C₆)aryl; (C₂-C₅)heteroaryl;(C₃-C₇)cycloalkyl; (C₁-C₈)alkoxy; (C₆)aryloxy; CN; OH; oxo; halo, CO₂H;NH₂; NH((C₁-C₈)alkyl); N((C₁-C₈)alkyl)₂; NH((C₆)aryl); N((C₆)aryl)₂;CHO; CO((C₁-C₈)alkyl); CO(C₆)aryl); CO₂((C₁-C₈)alkyl); andCO₂((C₆)aryl). One of skill in art can readily choose a suitablesubstituent based on the stability and pharmacological and syntheticactivity of the paclitaxel solubilizer of the invention.

[0090] As used herein, a “PEG-vitamin E” means a compound of theformula:

[0091] wherein the variable x is 0 or 1 and the variable n is about 1 toabout 20,000, preferably, from about 3 to about 1000. Preferably, thePEG-vitamin E is α-tocopheryl polyethylene glycol 1000 succinate,referred to herein as tocophersolan (sold by Eastman Chemical Co. underthe trade name vitamin E TPGS NF). In tocophersolan, x is 1 and n has anaverage value of 22. Other preferred PEG-vitamin Es, includetocophereth-5, tocophereth-10, tocophereth-12, tocophereth-18, andtocophereth-50. In such tocophereths, x is 0 and the averageethoxylation value is 5, 10, 12, 18, and 50 respectively. PEG-vitamin Esare available commercially, for example, from Eastman Chemical Co.,Kingsport, Tenn. and Pacific Corporation, Seoul, Korea.

[0092] As used herein, a quaternary ammonium salt means a compound ofthe general formula:

[0093] wherein R¹, R², R³, R⁴ are independently selected from the groupconsisting of (C₁-C₂₅)alkyl, aryl, (C₁-C₂₅)alkylaryl, (C₂-C₂₅)alkenyl,(C₂-C₂₅)alkynyl, (C₂-C₂₅)alkenylaryl, (C₂-C₂₅)alkynylaryl, phenyl, andbenzyl.

[0094] The group X is a suitable anion, for example, but not limited to,halide, acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate,calcium edetate, camsylate, carbonate, citrate, edetate, edisylate,estolate, esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydroxynaphthoate, isethionate, lactate, lactobionate, malate, maleate,mandelate, mesylate, methylbromide, methylnitrate, methylsulfate,muscate, napsylate, nitrate, pamoate (embonate), panthothenate,phosphate/diphosphate, polygalacturonate, salicylate, stearate,subacetate, succinate, sulfate, tannate, tartrate, teoclate, andtriethiodide. Preferred quaternary ammonium salts include, but are notlimited to, benzethonium chloride, benzalkonium chloride, and cetrimide.

[0095] As used herein, the term “polyethylene glycol of a fatty alcohol(PEG-fatty alcohol)” means a compound of the formula:

C₈H₁₇—A—B—(OCH₂CH₂)_(n)—OH

[0096] wherein n has an average value of about 1 to about 75; thevariable “A” represents the optional presence of one or morecarbon-carbon double bonds and the variable “B” represents(C₁-C₁₅)alkyl. Preferred PEG-fatty alcohols are octoxynols, oleths, andlaureths. As used herein, an “octoxynol” is a compound of the formula:

C₈H₁₇—C₆H₄—(OCH₂CH₂)_(n)—OH

[0097] wherein n is an integer having an average value of about 1 toabout 75, preferably, n has an average value of 1, 3, 5, 7, 8, 9, 10,11, 12, 13, 16, 20, 25, 30, 33, 40, or 70, more preferably, n has anaverage value of about 7 to 12, more preferably about 9. Preferredoctoxynols include octoxynol-9 (Triton® X-100). Octoxynols arecommercially available, for example, from Rhône-Poulenc, Shelton, Conn.under the trade name TRITON.

[0098] As used herein, an “oleth” is a compound of the formula:

[0099] wherein n is an integer having an average value of about 1 toabout 55, preferably, n has an average value of 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 15, 16, 20, 25, 40, 44, or 50, more preferably, n has anaverage value of about 7 to 12, more preferably about 9. Oleths arecommercially available, for example, from ICI Surfactants, Wilmington,Del. under the trade name BRIJ or from Heterene, Inc., Paterson, N.J.under the trade name HETOXOL.

[0100] As used herein, a “laureth” is a compound of the formula:

C₈H₁₇—C₄H₈—(OCH₂CH₂)_(n)—OH

[0101] wherein n is an integer having an average value of about 1 toabout 55, preferably, n has an average value of 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 15, 16, 20, 23, 25, 30, or 40 more preferably, n has anaverage value of about 7 to 12, more preferably about 23 (i.e.,laureth-23 also known as BRIJ 35, ICI Surfactants). Laureths arecommercially available, for example, from ICI Surfactants, Wilmington,Del. under the trade name BRIJ or from Rhône-Poulenc, Shelton, Conn.under the trade name RHODASURF.

[0102] As used herein, the term “polysorbate” means a compound of thegeneral formula:

[0103] wherein the sum of W+X+Y+Z is an integer having an average valueof about 5, 4, or 20; R⁵, R⁶, and R⁷ are independently H,

[0104] and n is an integer ranging from 8 to 20. Preferred polysorbatesare polysorbate 20, 21, 40, 60, 61, 65, 80, 81, 85, more preferablypolysorbate 20 or polysorbate 80. Polysorbates are availablecommercially under the trade name TWEEN from Rhône-Poulenc, Shelton,Conn.

[0105] As used herein, the term “polyethyleneglycol monoacid fattyester” (PEG-monoacid fatty ester) means a compound of the generalformula:

[0106] where R⁸ is (C₁-C₂₅)alkenyl, (C₂-C₂₅)alkenyl, or (C₂-C₂₅)alkynyl,in substantially pure form. As used herein, “substantially pure form”means that at least about 85% of polyethyleneglycol monoacid fatty esteris a single polyethyleneglycol monoacid fatty ester, preferably about95%. The variable m is an integer having an average value of from 2 to200, preferably, 6 to 150, more preferably, 10 to 50. Preferably, R⁸ is(C₈-C₂₀) or (C₈-C₂₀)alkenyl. Preferably, R⁸(CO)O is laurate, oleate, orstearate. Preferred PEG-monoacid fatty esters include, but are notlimited to, PEG-20 monolaurate, PEG-20 monooleate, and PEG-20monostearate.

[0107] As used herein, the term “polyethyleneglycol-glyceryl fattyester” (PEG-glyceryl fatty ester) means a compound of the generalformula: where R⁹ is independently OH, OCOR⁸, (OCH₂CH₂)_(m)OH, or(OCH₂CH₂)_(m)OCOR⁸, wherein:

[0108] (a) at least one of R⁹ is OCOR⁸ and one of R⁹ is (OCH₂CH₂)_(m)OH;or

[0109] (b) at least one of R⁹ is (OCH₂CH₂)_(m)OCOR⁸.

[0110] R⁸ is (C₁-C₂₅)alkyl, (C₂-C₂₅)alkenyl, or (C₂-C₂₅)alkynyl. And Thevariable m is an integer having an average value of from 2 to 200,preferably, 6 to 150, more preferably, 10 to 50. Preferably, R⁸ is(C₈-C₂₀) or (C₈-C₂₀)alkenyl. Preferably R⁸(CO)O is laurate, oleate, orstearate.

[0111] A subclass of PEG-glyceryl fatty esters has the formula:

[0112] where R⁸ is (C₁-C₂₅)alkyl, (C₂-C₂₅)alkenyl, or (C₂-C₂₅)alkynyl.And R⁹ is independently OH, OCOR⁸, (OCH₂CH₂)_(m)OH, or(OCH₂CH₂)_(m)OCOR⁸, wherein at least one of R⁹ is (OCH₂CH₂)_(m)OH or(OCH₂CH₂)_(m)OCOR⁸. The variable m is an integer having an average valueof from 2 to 200, preferably, 6 to 150, more preferably, 10 to 50.Preferably, R⁸ is (C₈-C₂₀) or (C₈-C₂₀)alkenyl. Preferably R⁸(CO)O islaurate, oleate, or stearate.

[0113] A further subclass of PEG-glyceryl fatty esters has the formula:

[0114] Wherein R⁸ is defined as above. Preferred PEG-glyceryl fattyesters include, but are not limited to, PEG-20 glyceryl monooleate,PEG-20 glyceryl monostearate, and PEG-20 glyceryl monolaurate.

4. DETAILED DESCRIPTION OF THE INVENTION

[0115] The invention encompasses cremophor-free formulations comprisingpaclitaxel, derivatives, or pharmaceutically acceptable salts thereofand one or more paclitaxel solubilizers that are useful for use inmammals, particularly humans. Paclitaxel solubilizers of the inventioninclude compounds falling within the classes of PEG-Vitamin Es;quaternary ammonium salts; PEG-monoacid fatty esters; PEG-glyceryl fattyesters; polysorbates; PEG-fatty alcohols. These formulations areadvantageous in that they do not contain cremophor and thus avoid orreduce the toxicities and other disadvantages of cremophor formulations.The formulations of the invention also solubilize paclitaxel in aqueousmedium and thus are particularly advantageous because paclitaxel ispractically insoluble in water.

[0116] The formulations of the invention are useful for treatingmammalian cancers and other medical conditions treatable by paclitaxel.By “treating” it is meant that the formulations are administered toinhibit or reduce the rate of cancer-cell proliferation in an effort toinduce partial or total remission, for example, inhibiting cell divisionby promoting microtubule formation. For instance, the formulations ofthe invention are useful for treating solid tumors and blood-borntumors. Examples of cancers treatable or preventable by formulations ofthe invention include, but are not limited to, cancers of the lymphnode; breast; cervix; uterus; gastrointestinal tract; lung; ovary;prostate; mouth; brain; head; neck; throat; testes; kidney; pancreas;bone; spleen; liver; bladder; skin; larynx; nasal passages; AIDS-relatedcancers, and cancers of the blood. The formulations can be used alone orin combination with other chemotherapeutics. The mode, dosage, andschedule of administration of paclitaxel, derivatives, andpharmaceutically acceptable salts thereof in human cancer patients havebeen extensively studied, see, e.g. 1989 Ann. Int. Med., 111:273-279,incorporated herein by reference.

[0117] The invention encompasses single-unit dosage forms and multi-unitdosage forms of paclitaxel, derivatives, and pharmaceutically acceptablesalts thereof in solid, liquid, semisolid, gel, suspension, emulsion, orsolution form. In one embodiment, the invention relates to single-unitdosage and multi-unit dosage forms. In another embodiment, the inventionrelates to single-unit dosage and multi-unit dosage forms ofliquid-concentrates, solids, semi-solids, and gels in concentrated formfor further formulation (e.g. lyophilized solids and liquid concentratesfor reconstitution prior to parenteral administration). Formulations ofthe invention in liquid-concentrate form are, preferably, in an organicsolvent, such as ethanol or aqueous ethanol, that is to be diluted withan aqueous medium prior to administration. Preferably, the formulationsare easy to handle, stable for storage and shipment, and inexpensive tomanufacture compared to previous paclitaxel formulations. Preferably,the formulations of the invention are sterile.

[0118] The formulations of the invention can be prepared by combiningthe actives, solubilizers of the invention, and other components usingwell-known pharmaceutical-formulation methods. Formulation of liquiddosage forms, such as for intravenous administration is described inRemington: the Science and Practice of Pharmacy, Alfonso R. Gennaro ed.,Mack Publishing Co. Easton, Pa., 19th ed., 1995, Chapters 87 and 88;incorporated herein by reference. A comprehensive discussion onformulating solid forms, such as powders, tablets, pills, and capsulesis presented in Remington: the Science and Practice of Pharmacy, AlfonsoR. Gennaro ed., Mack Publishing Co. Easton, Pa., 19th ed., 1995,Chapters 91 and 92, incorporated herein by reference. A comprehensivediscussion on formulating solutions, emulsions, and suspensions ispresented in Remington: the Science and Practice of Pharmacy, Alfonso R.Gennaro ed., Mack Publishing Co. Easton, Pa., 19th ed., 1995, Chapter86, incorporated herein by reference. Formulations of the invention inthe form of gels and semisolids containing the active can be preparedaccording to well known methods. For instance, by mixing the active withthe paclitaxel solubilizers of the invention, and any additionalcomponents or excipients in a standard V-blender. Preferably, forreconstitution, solids (e.g., lyophilized solids), liquid concentrates,semisolids, gels, suspensions, and emulsions, contain about 25milligrams to about 2500 milligrams of active, more preferably, about 50milligrams to about 500 milligrams.

[0119] The paclitaxel solubilizers of the invention are used informulations of the invention in amounts that enhance the solubility ofpaclitaxel, derivatives, and pharmaceutically acceptable salts thereofin an aqueous medium. Armed with the present disclosure that specifiesspecific paclitaxel solubilizers and combinations thereof that enhancethe aqueous solubility of paclitaxel, derivatives, and pharmaceuticallyacceptable salts thereof, one of skill in the art can readily determinesuitable paclitaxel-solubilizer amounts by simple solubilityexperiments. For example, by mixing the paclitaxel solubilizer and theactive, contacting the resulting mixture with an aqueous medium,filtering, and measuring the amount of dissolved active, for example, byspectrophotometry.

[0120] In one embodiment, the amount(s) of paclitaxel solubilizer informulations of the invention can be expressed as a ratio relative tothe amount of active. This is particularly useful when formulating aformulation of the invention in other than liquid form, e.g., solid,semisolid, gel, suspension, or emulsion, for example, a lyophilizedsolid. Preferred ratios of paclitaxel solubilizers to paclitaxel,derivatives, and pharmaceutically acceptable salts thereof are asfollows: Preferred ratio of paclitaxel More preferred ratio ofsolubilizer expressed as unit paclitaxel solubilizer weight per unitweight of expressed as unit weight per paclitaxel, derivative, or unitweight of paclitaxel, Excipient Class salt thereof derivative, or saltthereof PEG-Vitamin Es about 5 to about 200 about 10 to about 100Quaternary ammonium salts about 0.01 to about 1 about 0.016 to about 0.3PEG-monoacid fatty esters about 5 to about 200 about 10 to about 100PEG-glyceryl fatty esters about 5 to about 200 about 10 to about 100Polysorbates about 5 to about 200 about 10 to about 100 PEG-fattyalcohols about 5 to about 200 about 10 to about 100

[0121] In another embodiment, the formulations of the invention comprisean aqueous medium. Preferably, such a formulation is suitable forparenteral administration. In this embodiment, the preferredconcentration of paclitaxel, a derivative, or a salt thereof is fromabout 0.2 mg/ml to about 3 mg/ml, more preferably, about 0.3 mg/ml toabout 1.2 mg/ml. Preferred concentrations of paclitaxel solubilizers foruse with aqueous paclitaxel solutions of the invention are as follows:Preferred concentrations of More preferred concentrations paclitaxelsolubilizers in an of paclitaxel solubilizers in Excipient Class aqueousmedium (mg/ml) an aqueous medium (mg/ml) PEG-Vitamin Es about 3 to about120 about 15 to about 100 Quaternary ammonium salts about 0.0048 toabout 0.35 about 0.001 to about 0.2 PEG-monoacid fatty esters about 3 toabout 120 about 15 to about 100 PEG-glyceryl fatty esters about 3 toabout 120 about 15 to about 100 Polysorbates about 3 to about 120 about15 to about 80 PEG-fatty alcohols about 3 to about 120 about 15 to about110

[0122] In another embodiment, the formulations of the invention are inliquid-concentrate form. Liquid concentrate meaning that theformulations are to be diluted prior to parenteral administration,preferably, diluted with an aqueous medium. Preferably, liquidconcentrates of the invention have less than about 5% by weight water,more preferably, less than about 1%, even more preferably, liquidconcentrates are substantially anhydrous. Preferably, the concentrationof paclitaxel in liquid concentrates of the invention is from about 3mg/ml to about 10 mg/ml, more preferably, about 6 mg/ml. Paclitaxelsolubilizers of the invention can comprise about 0.1% to about 99% byweight of liquid-concentrate formulations of the invention. Preferably,liquid concentrates of the invention comprise about 20% to about 99%total solubilizer weight, e.g., about 20% to about 99% total weight ofone or more of a PEG-vitamin E, a PEG-monoacid fatty ester, aPEG-glyceryl fatty ester, a polysorbate, or a PEG-fatty alcohol. Thus,preferably, in a liquid-concentrate formulations, when one paclitaxelsolubilizer of the invention is used in combination with one or moreother paclitaxel solubilizers of the invention, the totalpaclitaxel-solubilizer weight percent is from about 20% to about 99%.Preferably, when combinations of paclitaxel solubilizers are used inliquid-concentrate formulations, each individual paclitaxel solubilizer(excluding the class of quaternary ammonium salts) represents at leastabout 5% by weight of the total paclitaxel-solubilizer weight. When aquaternary ammonium salt is included in a liquid-concentrate formulationof the invention, the preferred concentration is about 0.005 mg/ml toabout 5 mg/ml.

[0123] A few preferred liquid concentrate formulations of the invention(i.e., formulations 1-13) are shown below. Formulation 1 Preferredweight % Component Weight % range range Paclitaxel 0.1% to 1% 0.1% to 1%*PEG-400 0.1% to 99% 2.5% to 92.5% *Polysorbate 80 0.1% to 99% 2.5% to92.5% Ethanol 0% to 49% 5% to 59% Benzethonium chloride 0% to 0.2% 0% to0.2% Citric acid 0.01% to 1% 0.01% to 1%

[0124] Formulation 2 Preferred weight % Component Weight % range rangePaclitaxel 0.1% to 1% 0.1% to 1% *PEG-20 glyceryl 0.1% to 99% 2% to 93%monooleate Ethanol 0% to 59% 5% to 69% *Polysorbate 80 0.1% to 99% 2% to93% Benzethonium chloride 0% to 0.2% 0% to 0.2% Citric acid 0.01% to 1%0.01% to 1%

[0125] Formulation 3 Preferred weight % Component Weight % range rangePaclitaxel 0.1% to 1% 0.1% to 1% *PEG-20 glyceryl 0.1% to 99% 1% to 94%monooleate Ethanol 0% to 79% 5% to 79% *Vitamin E TPGS 0.1% to 99% 1% to94% Benzethonium chloride 0% to 0.2% 0% to 0.2% Citric acid 0.01% to 1%0.01% to 1%

[0126] Formulation 4 Preferred weight % Component Weight % range rangePaclitaxel 0.1% to 1% 0.1% to 1% *PEG-20 glyceryl 0.1% to 99% 2% to 93%monooleate Ethanol 0% to 59% 5% to 69% *PEG-20 monolaurate 0.1% to 99%2% to 93% Benzethonium chloride 0% to 0.2% 0% to 0.2% Citric acid 0.01%to 1% 0.01% to 1%

[0127] Formulation 5 Preferred weight % Component Weight % range rangePaclitaxel 0.1% to 1% 0.1% to 1% *PEG-20 glyceryl 0.1% to 99% 2% to 93%monooleate Ethanol 0% to 59% 5% to 69% *Polysorbate 20 0.1% to 99% 2% to93% Benzethonium chloride 0% to 0.2% 0% to 0.2% Citric acid 0.01% to 1%0.01% to 1%

[0128] Formulation 6 Preferred weight % Component Weight % range rangePaclitaxel 0.1% to 1% 0.1% to 1% *PEG-20 glyceryl 0.1% to 99% 2% to 93%monooleate Ethanol 0% to 59% 5% to 69% *PEG-20 monooleate 0.1% to 99% 2%to 93% Benzethonium chloride 0% to 0.2% 0% to 0.2% Citric acid 0.01% to1% 0.01% to 1%

[0129] Formulation 7 Preferred weight % Component Weight % range rangePaclitaxel 0.1% to 1% 0.1% to 1% Ethanol 0% to 79% 5% to 79% Vitamin ETPGS 20% to 99% 20% to 94% Benzethonium chloride 0% to 0.2% 0% to 0.2%Citric acid 0.01% to 1% 0.01% to 1%

[0130] Formulation 8 Preferred weight % Component Weight % range rangePaclitaxel 0.1% to 1% 0.1% to 1% Ethanol 0% to 80% 5% to 80% *Vitamin ETPGS 0.1% to 99% 1% to 94% *PEG-400 0.1% to 99% 1% to 94% Benzethoniumchloride 0% to 0.2% 0% to 0.2% Citric acid 0.01% to 1% 0.01% to 1%

[0131] Formulation 9 Preferred weight % Component Weight % range rangePaclitaxel 0.1% to 1% 0.1% to 1% Ethanol 0% to 80% 5% to 80% *Vitamin ETPGS 0.1% to 99% 1% to 94% *PEG-20 monooleate 0.1% to 99% 1% to 94%Benzethonium chloride 0% to 0.2% 0% to 0.2% Citric acid 0.01% to 1%0.01% to 1%

[0132] Formulation 10 Preferred weight % Component Weight % range rangePaclitaxel 0.1% to 1% 0.1% to 1% Ethanol 0% to 80% 5% to 80% *Vitamin ETPGS 0.1% to 99% 1% to 94% *Polysorbate 80 0.1% to 99% 1% to 94%Benzethonium chloride 0% to 0.2% 0% to 0.2% Citric acid 0.01% to 1%0.01% to 1%

[0133] Formulation 11 Preferred weight % Component Weight % range rangePaclitaxel 0.1% to 1% 0.1% to 1% Ethanol 0% to 80% 5% to 80% *Vitamin ETPGS 0.1% to 99% 1% to 94% *Polysorbate 20 0.1% to 99% 1% to 94%Benzethonium chloride 0% to 0.2% 0% to 0.2% Citric acid 0.01% to 1%0.01% to 1%

[0134] Formulation 12 Preferred weight % Component Weight % range rangePaclitaxel 0.1% to 1% 0.1% to 1% Ethanol 0% to 80% 5% to 80% *Vitamin ETPGS 0.1% to 99% 1% to 94% *PEG-20 monolaurate 0.1% to 99% 1% to 94%Benzethonium chloride 0% to 0.2% 0% to 0.2% Citric acid 0.01% to 1%0.01% to 1%

[0135] Formulation 13 Preferred weight % Component Weight % range rangePaclitaxel 0.1% to 1% 0.1% to 1% Ethanol 0% to 70% 5% to 70%*Polysorbate 80 0.1% to 99% 1% to 94% *PEG-20 monooleate 0.1% to 99% 1%to 94% Benzethonium chloride 0% to 0.2% 0% to 0.2% Citric acid 0.01% to1% 0.01% to 1%

[0136] The formulations of the invention can include additionalpharmaceutically acceptable excipients. Preferred additional excipientsdo not affect the ability of the paclitaxel solubilizers of theinvention to solubilize paclitaxel. Preferred additional excipients forintravenous administration are water, aqueous vehicles such as saline,Ringer's solution, or dextrose solution. Other examples of suitableexcipients, such as binders and fillers are listed in Remington: theScience and Practice of Pharmacy, 18th Edition, ed. Alfonso Gennaro,Mack Publishing Co. Easton, Pa., 1995 and Handbook of PharmaceuticalExcipients, 3rd Edition, ed. Arthur H. Kibbe, American PharmaceuticalAssociation, Washington D.C. 2000. Whatever excipient is incorporatedinto the present formulations, preferably, that excipient is sterilewhen added, or sterilized during the same process that sterilizes theformulation.

[0137] Administration of formulations of the invention can be systemicor local. In most instances, administration to a mammal will result insystemic release of the active (i.e., into the bloodstream). Methods ofadministration include enteral routes, such as oral administration;topical routes, such as local, transdermal and intradermaladministration; and parenteral routes, such as intravenous injection.Preferably, the formulations of the invention are administeredintravenously.

[0138] Typically, formulation of the invention for parenteraladministration are solutions in sterile isotonic aqueous vehicles, suchas water, saline, Ringer's solution, or dextrose solution. Formulationsfor intravenous administration may optionally include a local anestheticsuch as lignocaine to ease pain at the site of the injection. Forparenteral administration, the formulations of the invention can besupplied as a sterile, dry lyophilized powder or a water-free liquidconcentrate in a hermetically sealed container, such as an ampoule or ani.v. bag, the container indicating the quantity of active. Such a powderor concentrate is then diluted with an appropriate aqueous medium priorto administration. An ampoule of sterile water, saline solution, orother appropriate aqueous medium can be provided with the powder orconcentrate in a separate container to dilute the active prior toadministration. Alternatively, the formulations can be supplied inpre-mixed form, ready for administration.

[0139] A further embodiment of the present invention includes asterilization step. The sterilization may be carried out in severalways, e.g., by using a bacteriological filter, by incorporatingsterilizing agents into the composition, by irradiation, or by heating.Sterilization may be effected, for example, by filtration through a 0.2μm pore size filter. Other methods of sterilizing well known to thoseskilled in the art can also be employed.

[0140] To formulate aqueous parenteral dosage forms, an aqueous medium,e.g., physiological saline or purified water, paclitaxel solubilizers,and any additional components are mixed in sanitized equipment,filtered, and packaged according to well known methods in the art (for adiscussion see e.g., Remington: the Science and Practice of Pharmacy,Alfonso R. Gennaro ed., Mack Publishing Co. Easton, Pa., 19th ed., 1995,Chapter 87). For parenteral administration the dosage will, of course,vary with the potency of the particular active based on potency, thepatient weight, and the nature of the patient's condition. The preferreddosage for intravenous administration is that listed in The Physician'sDesk Reference, 54th edition, 881-887, Medical Economics Company (2000).Dosages typically fall in the range of about 135 mg/m² to 400 mg/m²,preferably 175 mg/m², more preferably, 200 mg/m². An oncologist skilledin the art of cancer treatment will be able to ascertain appropriateprotocols for effective administration of the formulations of theinvention by referring to the earlier studies of paclitaxel,derivatives, and pharmaceutically acceptable salts thereof or thedosages listed in medical reference books.

[0141] Formulations of the invention for oral delivery are preferably inthe form of capsules, tablets, pills, soft-gel capsules, emulsions,solutions, or suspensions. Oral compositions can include standardvehicles, excipients, and diluents. Orally administered formulations ofthe invention can optionally include one or more sweetening agents andone or more flavoring agents to provide a pharmaceutically palatablepreparation. A therapeutically effective oral dosage for formulations ofthe invention is determined by standard clinical techniques according tothe judgment of a medical practitioner. For example, in addition toinformation provided in medical reference books and pharmaceuticalliterature, well-known in vitro or in vivo assays can be used to helpidentify optimal dosages.

[0142] To formulate and administer transdermal dosage forms, well knowntransdermal delivery devices such as patches can be used (Ghosh, T. K.;Pfister, W. R.; Yum, S. I. Transdermal and Topical Drug DeliverySystems, Interpharm Press, Inc. p. 249-297, incorporated herein byreference). For example, a reservoir type patch design can comprise abacking film coated with an adhesive, and a reservoir compartmentcomprising a formulation of the invention, that is separated from theskin by a semipermeable membrane (e.g., U.S. Pat. No. 4,615,699,incorporated herein by reference). The adhesive coated backing layerextends around the reservoir's boundaries to provide a concentric sealwith the skin and hold the reservoir adjacent to the skin.

[0143] To formulate and administer local dosage forms, well knownmediums such as lotions, creams, and ointments can be used.

[0144] The present formulations can include additional actives and thuscan serve as base formulation for combination therapy. Such additionalactives can be included and distributed in the formulation itself (e.g.,pre-diluted or in a form for reconstitution) or added to the formulationprior to administration. For example, the formulations of the inventionand other actives can be combined in an i.v. bag prior toadministration. Additional actives can be any pharmaceuticalconventionally administered with paclitaxel, for example, otherchemotherapeutics, such as, but not limited to, cisplatin, carboplatin,tamoxifen, epirubicin, leuprolide, bicalutamide, goserelin implant,irinotecan, gemcitabine, and sargramostim or pharmaceutically acceptablesalts thereof, preferably cisplatin. Thus, the formulations of theinvention encompass formulations comprising active, the paclitaxelsolubilizers of the invention, and other actives suitable forco-administration with paclitaxel.

[0145] The formulations of the invention can be packaged and distributedas a non-aqueous liquid-solution concentrates for dilution in an aqueousmedium prior to administration. For example, the present formulations inliquid-concentrate form or in the form of a lyophilized solid can beadded to an i.v. bag and diluted with an aqueous medium prior tointravenous infusion. Preferably, such concentrates comprise anon-aqueous solvent, the active, and one or more of the paclitaxelsolubilizers of the invention. Preferably, the non-aqueous solvent is anorganic solvent, such as ethanol. Thus, the formulations of theinvention in liquid-concentrate form can be packaged as ethanolsolutions, for example, packaged in a multi-unit-dose vial containing 30mg paclitaxel, the paclitaxel solubilizers, and about 0.2 ml to about 3ml ethanol or a multi-unit-dose vial containing 100 mg paclitaxel, thepaclitaxel solubilizers, and about 0.6 ml to 10 ml of ethanol.

[0146] The formulations of the invention, can be distributed incontainers that allow rapid dissolution of the formulation uponreconstitution with appropriate sterile diluents, in situ, giving anappropriate sterile solution of desired active concentration foradministration. As used herein, the term “suitable containers” means acontainer capable of maintaining a sterile environment, such as a vial,package, or bottle, capable of delivering a vacuum dried producthermetically sealed by a stopper means. Additionally, suitablecontainers implies appropriateness of size, considering the volume ofsolution to be held upon reconstitution of the vacuum dried composition;and appropriateness of container material, generally Type I glass. Thestopper means employed, e.g., sterile rubber closures or an equivalent,should be understood to be that which provides the aforementioned seal,but which also allows entry for the purpose of introduction of diluent,e.g., sterile Water for Injection, USP, Normal Saline, USP, or 5%Dextrose in Water, USP, for the reconstitution of the desired activesolution. These and other aspects of the suitability of containers forpharmaceutical products such as those of the invention are well known tothose skilled in the practice of pharmaceutical arts.

[0147] The present invention will be further understood by reference tothe following non-limiting examples. The following examples are providedfor illustrative purposes only and are not to be construed as limitingthe invention scope of the invention in any manner.

5. EXAMPLES Example 1

[0148] Preparation and Identification of Aqueous Paclitaxel Formulationswith Enhanced Solubility.

[0149] A plurality of aqueous formulations, each containing paclitaxeland various combinations and concentrations of the excipients listed inTable 1 below were prepared and systematically analyzed for theirability to dissolve paclitaxel.

[0150] The GRAS (“generally regarded as safe”) excipients listed inTable 1 are all obtainable from Sigma-Aldrich Fine Chemicals, BASF, orother commercial suppliers. TABLE 1 Excipients Used in the Examples 1γ-Cyclodextrin 2 β-Cyclodextrin 3 Diethanolamine 4 Propyleneglycol 5Glycerin 6 Poloxomer ® 188 7 Poloxomer ® 237 8 Poloxomer ® 338 9Poloxomer ® 407 10 Polyethyleneglycol 300 (PEG-300) 11Polyethyleneglycol 600 (PEG-600) 12 Polyethyleneglycol 1000 (PEG-1000)13 Polyethyleneglycol 4000 (PEG-4000) 14 Polysorbate 20 15 Polysorbate80 16 Polyethyleneglycol-20 monostearate (PEG-20 monostearate) 17Polyethyleneglycol-40 monostearate (PEG-40 monostearate) 18Polyethyleneglycol-50 monostearate (PEG-50 monostearate) 19 Cholinechloride Polyethyleneglycol-20 glyceryl monooleate (PEG-20 glycerylmonooleate) 20 Sodium caprylate 21 Polyethyleneglycol-100 monostearate(PEG-100monostearate) 22 Povidone 23 Deoxycholoate 24 Laureth-23 25Isosorbide dimethyl ether 26 Polyethyleneglycol-20 monooleate (PEG-20monooleate) 27 Polyethyleneglycol-20 monolaurate (PEG-20 monolaurate) 28Polyethyleneglycol-tetrahydrofurfuryl ether (PEG-tetrahydrofurfuryl) 29octoxynol-9 30 2-pyrrolidone 31 Benzethonium chloride 32 Benzalkoniumchloride 33 cetrimide 34 Polyethyleneglycol-l,2-diacyl-sn-glycerol-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (PEG-DSPE) 35Polyvinyl alcohol 36 tocophersolan 37 Sodium lauryl sulfate (SDS) 38Protamine sulfate 39 Laureth-23 40 Polyethyleneglycol-20 glycerylmonolaurate (PEG-20 glyceryl monolaurate)

[0151] Preparation of Formulations with Improved Solubilities

[0152] A stock solution comprising about 10 milligrams paclitaxel permilliliter ethanol was prepared. Then a plurality of excipients wereselected from Table 1 and each selected excipient was prepared as anaqueous solution, at various concentrations, for example, as threephysiological-saline stock solutions each at one of three setconcentrations, e.g. about 120 milligrams/milliliter, about 60milligrams/milliliter, and about 30 milligrams/milliliter. Then allpermutations of formulations that each comprise about 12 μl of thepaclitaxel/ethanol solution (about 120 μg of paclitaxel per sample well)and about 90 μl of one to three of the excipient stock solutions wereprepared.

[0153] All permutations of excipients stock solutions and paclitaxelwere generated using the MATLAB program formulating software(commercially available from Mathworks, Natick, Mass.). The permutationsso generated were downloaded into a Microsoft EXCEL spread sheet andfrom this spread sheet, a worklist was constructed according to standardprogramming methods well known to those skilled in the art. Thework-list is then used to direct the Genesis liquid-handling device toprepare the various permutations of excipients and paclitaxel generatedby MATLAB. The worklist combines the formulation output of the MATLABprogram with Genesis-appropriate commands (as found in the Genesisoperating manual) in a file format that is directly readable by theGenesis device. For example, the number of possible unique combinationswith 120 excipient stock solutions is:$\frac{\left( {120 + 3 - 1} \right)!}{{3!}{\left( {120 - 1} \right)!}} = {295,\quad 240}$

[0154] giving a grand total of 295,240 unique formulations. Theformulations were prepared in DYNEX 96 sample well polystyrene plates(available from Thermo Labsystems Oy, Helsinki, Finland). Each samplewell has a volume of 250 μl. Each sample formulation generated by theMATLAB program was prepared in triplicate by adding about 12 μl of thepaclitaxel/ethanol solution and about 30 μl of three of the excipientstock solution to each sample well. The stock solutions were added usinga Genesis liquid-handling device (Tecan-US, RTP, NC). The force providedby adding the excipient via the Genesis liquid-handling device wassufficient to adequately mix the components. The plates were sealed withaluminum sealing tapes and incubated at 25° C. for 48 hours before theywere measured on a UV plate reader at 500 nm (SpectraMax Plus, MolecularDevices, Sunnyvale, Calif.).

[0155] Results

[0156] The screening results, measured as turbidity at 500 nm for all ofthe samples were imported into a data analysis and visualization programSpotfire (Spotfire, Cambridge, Mass.) and samples that reproducibly (%standard deviation <5%) demonstrated an absorbance below 0.045 wereselected as hits. An absorbance below 0.045 indicates that thepaclitaxel was completely dissolved, i.e., the paclitaxel concentrationwas 1.2 mg/ml, and stayed dissolved for 48 hours. The selectedformulations along with concentrations of the paclitaxel solubilizersare listed in Table 2 below. Each of these examples can readily be usedto formulate paclitaxel into a suitable injectable dosage form.

[0157] The chemical stability of the paclitaxel formulations in Table 2was analyzed using a Waters Alliance 2790 HPLC equipped with a Waters996 Photo Diode Array Detector. The separation was carried out on aPhenomenex Curosil Pentafluorphenyl column (150×3.2 mm, 3 m) with amobile phase of 55% water and 45% acetonitrile, held isocratic at a flowrate of 0.5 ml/min. A control solution of paclitaxel (0.1 mg/ml) forcomparison was prepared from a stock solution of 1 mg/ml in ethanol bysub-dilution into acetonitrile. Each of the formulations of paclitaxelwere diluted in acetonitrile to a concentration of approximately 0.1mg/ml before HPLC analysis and absorbance was measured at 229 nm. Thechromatograph for each formulation was compared with the controlsolution. No degradation of Paclitaxel was observed for the selectedformulations, even after 48 hours incubation at RT in physiologicalsaline, establishing chemical stability of the formulations of theinvention. Using this general procedure with the 40 excipients listed inTable 1, the formulations listed in Table 2 were selected as stable andcapable of dissolving paclitaxel in an aqueous medium to a concentrationof 1.2 mg/ml. TABLE 2 Selected Formulations Conc. Conc. Conc. AbsExcipient mg/ml Excipient mg/ml Excipient mg/ml 0.039 polysorbate 80 18otoxynol-9 18 benzalkonium 18 chloride 0.039 polysorbate 80 18otoxynol-9 18 cetrimide 18 0.039 polysorbate 80 36 otoxynol-9 36 PEG-20monolaurate 36 0.039 polysorbate 80 36 otoxynol-9 36 PEG-20 monooleate36 0.040 polysorbate 80 36 otoxynol-9 72 0.039 polysorbate 20 36otoxynol-9 36 PEG-20 monolaurate 36 0.039 polysorbate 20 36 otoxynol-972 0.039 polysorbate 20 18 Sodium caprylate 18 cetrimide 18 0.040polysorbate 80 72 PEG-20 monooleate 36 0.040 polysorbate 80 36 PEG-20monooleate 72 0.040 polysorbate 20 36 PEG-20 monooleate 72 0.040polysorbate 80 72 PEG-20 monolaurate 36 0.040 polysorbate 80 36 PEG-20monolaurate 72 0.040 polysorbate 20 36 PEG-20 monolaurate 72 0.039polysorbate 80 18 benzethonium 18 PEG 1000 18 chloride 0.039 polysorbate20 36 2-pyrrolidone 36 octoxynol-9 36 0.039 octoxynol-9 36 benzalkonium18 chloride 0.039 octoxynol-9 36 PEG-20 monolaurate 36 PEG-20 monooleate36 0.038 octoxynol-9 72 PEG-20 monolaurate 36 0.040 octoxynol-9 36PEG-20 monolaurate 72 0.040 octoxynol-9 72 PEG-20 monooleate 36 0.038octoxynol-9 108 0.040 Isosorbide 36 octoxynol-9 36 PEG-20 monolaurate 36dimethyl ether 0.039 Isosorbide 36 octoxynol-9 72 dimethyl ether 0.039benzethonium 36 octoxynol-9 18 chloride 0.039 PEG- 36 octoxynol-9 36PEG-20 monolaurate 36 tetrahydrofurfuryl ether 0.039 benzethonium 18octoxynol-9 36 chloride 0.039 Sodium caprylate 18 octoxynol-9 18benzalkonium 18 chloride 0.038 benzethonium 18 octoxynol-9 18 cetrimide18 chloride 0.038 SDS 36 octoxynol-9 18 0.039 Povidone 18 SDS 18β-cyclodextrin 4.5 0.038 Sodium caprylate 18 SDS 36 0.039 benzethonium36 propylene glycol 18 chloride 0.038 SDS 36 propylene glycol 18 0.039benzethonium 36 cetrimide 18 chloride 0.040 benzethonium 36 benzalkonium18 chloride chloride 0.038 cetrimide 36 benzalkonium 18 chloride 0.040PEG-20 monooleate 108 0.039 benzethonium 54 chloride 0.038 SDS 54 0.040tocophersolan 60 protamine sulfate 3.06 0.040 tocophersolan 48 protaminesulfate 1.836 0.040 tocophersolan 60 PEG-20 monostearate 30 0.040tocophersolan 60 PEG-20 monostearate 18 0.042 tocophersolan 30 PEG-20monostearate 60 0.039 tocophersolan 48 PEG-20 monostearate 30 0.040tocophersolan 30 PEG-20 monostearate 48 0.040 tocophersolan 48 PEG-20monostearate 18 0.039 tocophersolan 36 PEG-20 monostearate 30 0.040tocophersolan 60 PEG 300 102 0.040 tocophersolan 60 PEG 300 61.2 0.040tocophersolan 48 PEG 300 61.2 0.040 tocophersolan 90 0,040 tocophersolan78 0.040 tocophersolan 66 0.040 tocophersolan 54 0.040 polysorbate 80 30tocophersolan 60 0.041 polysorbate 80 48 tocophersolan 30 0.040polysorbate 80 18 tocophersolan 60 0.041 polysorbate 80 36 tocophersolan30 0.040 polysorbate 80 36 tocophersolan 18 0.041 polysorbate 80 30tocophersolan 30 PEG-20 monostearate 18 0.040 polysorbate 80 30tocophersolan 18 PEG-20 monostearate 30 0.041 polysorbate 80 18tocophersolan 30 PEG-20 monostearate 30 0.043 polysorbate 80 18tocophersolan 30 protamine sulfate 3.06 0.040 polysorbate 20 30tocophersolan 60 0.040 polysorbate 20 18 tocophersolan 60 0.039polysorbate 20 36 tocophersolan 30 0.039 PEG-20 monooleate 30tocophersolan 60 0.039 PEG-20 monooleate 30 tocophersolan 48 0.040PEG-20 monooleate 18 tocophersolan 60 0.039 PEG-20 monooleate 30tocophersolan 30 PEG-20 monostearate 30 0.039 PEG-20 monolaurate 30tocophersolan 60 0.040 choline chloride 48 tocophersolan 30 0.040choline chloride 30 tocophersolan 48 0.040 choline chloride 18tocophersolan 60 0.040 choline chloride 18 tocophersolan 48 0.039laureth-23 30 tocophersolan 60 0.039 laureth-23 30 tocophersolan 480.041 laureth-23 18 tocophersolan 48 0.040 laureth-23 18 tocophersolan30 PEG-20 monostearate 18 0.039 polysorbate 80 18 PEG-20 monooleate 18tocophersolan 30 0.040 polysorbate 80 18 choline chloride 30tocophersolan 30 0.040 polysorbate 80 30 PEG-20 monooleate 60 0.042PEG-20 monostearate 66 0.040 PEG-20 monooleate 30 PEG-20 monostearate 600.040 PEG-20 monooleate 90 0.039 laureth-23 18 PEG-20 monooleate 18tocophersolan 30 0.038 PEG-20 glyceryl 100 polysorbate 80 40 monooleate0.039 PEG-20 glyceryl 100 polysorbate 80 60 monooleate 0.039 PEG-20glyceryl 100 polysorbate 80 80 monooleate 0.040 PEG-20 glyceryl 100PEG-20 monooleate 60 monooleate 0.039 PEG-20 glyceryl 100 PEG-20monooleate 80 monooleate 0.039 PEG-20 glyceryl 100 PEG-20 monolaurate 60monooleate 0.040 PEG-20 glyceryl 100 PEG-20 monolaurate 80 monooleate0.039 PEG-20 glyceryl 100 PEG-20 monolaurate 40 monooleate 0.040 PEG-20glyceryl 100 PEG-20 monolaurate 20 monooleate 0.038 PEG-20 glyceryl 100polysorbate 20 40 monooleate 0.039 PEG-20 glyceryl 100 polysorbate 20 60monooleate 0.039 PEG-20 glyceryl 100 polysorbate 20 80 monooleate 0.038PEG-20 glyceryl 100 tocophersolan 20 monooleate 0.038 PEG-20 glyceryl100 tocophersolan 40 monooleate 0.038 PEG-20 glyceryl 100 tocophersolan60 monooleate 0.039 PEG-20 glyceryl 100 tocophersolan 80 monooleate0.039 PEG-20 glyceryl 80 tocophersolan 100 monooleate 0.039 PEG-20glyceryl 60 tocophersolan 100 monooleate 0.040 PEG-20 glyceryl 40tocophersolan 100 monooleate 0.039 PEG-20 glyceryl 20 tocophersolan 100monooleate 0.040 tocophersolan 100 0.038 PEG-20 glyceryl 100tocophersolan 60 monolaurate 0.039 PEG-20 glyceryl 100 tocophersolan 80monolaurate 0.039 PEG-20 glyceryl 80 tocophersolan 100 monolaurate 0.039PEG-20 glyceryl 60 tocophersolan 100 monolaurate 0.040 PEG-20 glyceryl40 tocophersolan 100 monolaurate 0.039 PEG-20 glyceryl 20 tocophersolan100 monolaurate

[0158] Excipients classes that were present in at least 10 formulationslisted in Table 2 above and gave stable paclitaxel solutions wereselected as paclitaxel solubilizers of the invention (i.e., PEG-vitaminEs, quaternary ammonium salts, PEG-monoacid fatty esters, PEG-glycerylfatty esters, polysorbates, and PEG-fatty alcohols) first, because theywere present in formulations that dissolved paclitaxel to aconcentration of about 1.2 mg/ml and, second, by appearing at highfrequency, indicated that they interacted with paclitaxel or the othercomponents to facilitate dissolution of paclitaxel in an aqueous medium.TABLE 3 Paclitaxel Solubilizers of the Invention Excipient Class HitsPEG-Vitamin Es 59 Quaternary ammonium salts 14 PEG-monoacid fatty esters44 PEG-glyceryl fatty esters 20 Polysorbates 38 PEG-fatty alcohols 27

[0159] Preferred paclitaxel solubilizers are PEG-Vitamin Es, such astocophersolan; polysorbates, such as polysorbates 80 and 20;PEG-monoacid fatty esters, such as PEG-20 monooleate, PEG-20monolaurate, and PEG-20 monostearate; PEG-glyceryl fatty esters, such asPEG-20 glyceryl monooleate, PEG-20 glyceryl monostearate, and PEG-20glyceryl monolaurate; and PEG-fatty alcohols, such as octoxynols (e.g.,octoxynol-9), oleths, and laureths (e.g., laureth-23).

[0160] The data in Table 2 was further analyzed with respect to thepaclitaxel solubilizers of the invention (Table 3) to determinecombinations of excipients useful for solubilizing and administeringpaclitaxel, derivatives, and salts thereof.

[0161] Table 4 below lists excipients along with the excipient class,that appeared as a component with a PEG-vitamin E in the selectedformulations of Table 2 at a high frequency (i.e., at least 4 times).TABLE 4 Excipient Classes That in Combination with a PEG-vitamin Eprovide Formulations with a High Propensity to Dissolve Paclitaxel ClassExcipient Excipient hits Class hits PEG-monoacid PEG-20 monooleate 6 19fatty PEG-20 12 esters monostearate PEG-20 1 monolaurate PEG-glycerylPEG-20 glyceryl 8 14 fatty monooleate esters PEG-20 glyceryl 6monolaurate Polysorbates polysorbate 20 3 14 polysorbate 80 11 PEG-fattyoctoxynol-9 0 5 alcohols laureth-23 5

[0162] The data in Table 4 above demonstrates that PEG-vitamin Es incombination with excipient classes PEG-monoacid fatty esters,PEG-glyceryl fatty esters, polysorbates, or PEG-fatty alcohols interactto provide formulations useful for solubilizing paclitaxel.

[0163] Table 5 below lists excipients, along with the excipient class,that appeared as a component with a quaternary ammonium salt in theselected formulations of Table 2 at a high frequency. TABLE 5 ExcipientClasses That in Combination with a Quaternary Ammonium Salt ProvideFormulations with a High Propensity to Dissolve Paclitaxel ClassExcipient Excipient hits Class hits Polysorbates polysorbate 20 1 4polysorbate 80 3 PEG-fatty octoxynol-9 8 8 alcohols laureth-23 0

[0164] The data in Table 5 above demonstrates that quaternary ammoniumsalts in combination with excipient classes polysorbates or PEG-fattyalcohols interact to provide formulations useful for solubilizingpaclitaxel.

[0165] Table 6 below lists excipients, along with the excipient class,that appeared as a component with a PEG-monoacid fatty esters in theselected formulations of Table 2 at a high frequency. TABLE 6 ExcipientClasses That in Combination with a PEG-monoacid Fatty Ester ProvideFormulations with a High Propensity to Dissolve Paclitaxel ClassExcipient Excipient hits Class hits PEG-Vitamin Es tocophersolan 18 18Polysorbates polysorbate 20 2 11 polysorbate 80 9 PEG-fatty octoxynol-94 6 alcohols laureth-23 2 PEG-glyceryl PEG-20 glyceryl 6 6 fattymonooleate esters PEG-20 glyceryl 0 monolaurate

[0166] The data in Table 6 above demonstrates that PEG-monoacid fattyesters in combination with excipient classes PEG-vitamin Es,polysorbates, PEG-fatty alcohols, or PEG-glyceryl fatty esters interactto provide formulations useful for solubilizing paclitaxel.

[0167] Table 7 below lists excipients, along with the excipient class,that appeared as a component with a polysorbate in the selectedformulations of Table 2 at a high frequency. TABLE 7 Excipient ClassesThat in Combination with a PEG-Glyceryl fatty esters ProvideFormulations with a High Propensity to Dissolve Paclitaxel ClassExcipient Excipient hits Class hits PEG-Vitamin Es tocophersolan 14 14Polysorbates polysorbate 20 3 6 polysorbate 80 3 PEG-monoacid fattyPEG-20 monooleate 2 6 esters PEG-20 monostearate 0 PEG-20 monolaurate 4

[0168] The data in Table 7 above demonstrates that PEG-glyceryl fattyesters in combination with excipient classes PEG-vitamin Es,polysorbates, or PEG-monoacid fatty esters interact to provideformulations useful for solubilizing paclitaxel.

[0169] Table 8 below lists excipients, along with the excipient class,that appeared as a component with a polysorbate in the selectedformulations of Table 2 at a high frequency. TABLE 8 Excipient ClassesThat in Combination with a Polysorbate Provide Formulations with a HighPropensity to Dissolve Paclitaxel Excipient Class Class Excipient hitshits PEG-Vitamin Es tocophersolan 14 14 Quaternary ammonium benzalkonium1 4 salts chloride benzethonium 1 chloride cetrimide 2 PEG-monoacidfatty PEG-20 monooleate 5 13 esters PEG-20 monostearate 3 PEG-20monolaurate 5 PEG-glyceryl fatty PEG-20 glyceryl 6 6 esters monooleatePEG-20 glyceryl 0 monolaurate PEG-fatty alcohols octoxynol-9 8 8laureth-23 0

[0170] The data in Table 8 above demonstrates that polysorbates incombination with excipient classes PEG-vitamin Es, quaternary ammoniumsalts, PEG-monoacid fatty esters, PEG-glyceryl fatty esters, orPEG-fatty alcohols, interact to provide formulations useful forsolubilizing paclitaxel.

[0171] Table 9 below lists excipients, along with the excipient class,that appeared as a component with a PEG-fatty alcohol in theformulations of Table 2 at a high frequency. TABLE 9 Excipient ClassesThat in Combination with a PEG-fatty Alcohol Provide Formulations with aHigh Propensity to Dissolve Paclitaxel Excipient Class Class Excipienthits hits PEG-Vitamin Es tocophersolan 5 5 Quaternary ammoniumbenzalkonium 3 8 salts chloride benzethonium 3 chloride cetrimide 2PEG-monoacid fatty PEG-20 monooleate 4 12 esters PEG-20 monostearate 1PEG-20 monolaurate 7 Polysorbates polysorbate 20 3 8 polysorbate 80 5

[0172] The data in Table 9 above demonstrates that PEG-fatty alcohols incombination with excipient classes PEG-vitamin Es, quaternary ammoniumsalts, PEG-monoacid fatty esters, or polysorbates interact to provideformulations useful for solubilizing paclitaxel.

Example 2

[0173] Preparation of Liquid-Concentrate Paclitaxel Formulations withEnhanced Aqueous Solubility

[0174] The following liquid-concentrate paclitaxel formulations wereprepared by mixing paclitaxel, the paclitaxel solubilizers, andadditional components using standard pharmaceutical-formulationprocedures. Formulation A Component Weight % weight Paclitaxel 6 mg 0.6% PEG-400 294 mg 29.2% Polysorbate 80 485 mg 48.1% Ethanol 221 mg21.9% Citric acid 2 mg  0.2%

[0175] Formulation B Component Weight % weight Paclitaxel 6 mg  0.6%PEG-20 glyceryl monooleate 500 mg 49.6% Ethanol 300 mg 29.8% Polysorbate80 200 mg 19.8% Citric acid 2 mg  0.2%

[0176] Formulation C Component Weight % weight Paclitaxel 6 mg 0.6%PEG-20 glyceryl monooleate 500 mg 49.6%  Ethanol 400 mg 39.7%  Vitamin ETPGS 100 mg 9.9% Citric acid 2 mg 0.2%

[0177] Formulation D Component Weight % weight Paclitaxel 6 mg  0.6%PEG-20 glyceryl monooleate 500 mg 49.6 Ethanol 300 mg 29.8 PEG-20monolaurate 200 mg 19.8 Citric acid 2 mg  0.2%

[0178] Formulation E Component Weight % weight Paclitaxel 6 mg  0.6%PEG-20 glyceryl monooleate 500 mg 49.6% Ethanol 300 mg 29.8% Polysorbate20 200 mg 19.8% Citric acid 2 mg  0.2%

[0179] Formulation F Component Weight % weight Paclitaxel 6 mg  0.6%PEG-20 glyceryl monooleate 500 mg 49.6% Ethanol 200 mg 19.8% PEG-20monooleate 300 mg 29.8% Citric acid 2 mg  0.2%

[0180] Formulation G Component Weight % weight Paclitaxel 6 mg 0.6%Ethanol 500 mg 49.6%  Vitamin E TPGS 500 mg 49.6%  Citric acid 2 mg 0.2%

[0181] Formulation H Component Weight % weight Paclitaxel 6 mg 0.6%Ethanol 400 mg 39.7%  Vitamin E TPGS 500 mg 49.6%  PEG-400 100 mg 9.9%Citric acid 2 mg 0.2%

[0182] Formulation I Component Weight % weight Paclitaxel 6 mg 0.6%Ethanol 400 mg 39.7%  Vitamin E TPGS 500 mg 49.6%  PEG-20 monooleate 100mg 9.9% Citric acid 2 mg 0.2%

[0183] Formulation J Component Weight % weight Paclitaxel 6 mg 0.6%Ethanol 400 mg 39.7%  Vitamin E TPGS 500 mg 49.6%  Polysorbate 80 100 mg9.9% Citric acid 2 mg 0.2%

[0184] Formulation K Component Weight % weight Paclitaxel 6 mg 0.6%Ethanol 400 mg 39.7%  Vitamin E TPGS 500 mg 49.6%  Polysorbate 20 100 mg9.9% Citric acid 2 mg 0.2%

[0185] Formulation L Component Weight % weight Paclitaxel 6 mg 0.6%Ethanol 400 mg 39.7%  Vitamin E TPGS 500 mg 49.6%  PEG-20 monolaurate100 mg 9.9% Citric acid 2 mg 0.2%

[0186] Formulation M Component Weight % weight Paclitaxel 6 mg  0.6%Ethanol 559 mg 55.4% Polysorbate 80 294 mg 29.2% PEG-20 monooleate 147mg 14.6% Citric acid 2 mg  0.2%

[0187] Formulation N Component Weight % weight Paclitaxel 6 mg  0.6%PEG-400 500 mg 49.6% Polysorbate 80 300 mg 29.8% Ethanol 200 mg 19.9%Citric acid 2 mg  0.2%

[0188] Formulation O Component Weight % weight Paclitaxel 6 mg  0.6%PEG-400 500 mg 49.6% Ethanol 150 mg 14.9% Polysorbate 80 350 mg 34.7%Citric acid 2 mg  0.2%

[0189] Formulation P Component Weight % weight Paclitaxel 6 mg  0.6%PEG-20 glyceryl monooleate 400 mg 39.7% Ethanol 400 mg 39.7% Polysorbate80 200 mg 19.9% Citric acid 2 mg  0.2%

[0190] Formulation Q Component Weight % weight Paclitaxel 6 mg  0.6%PEG-20 glyceryl monooleate 300 mg 29.8% Ethanol 500 mg 49.6% Polysorbate80 200 mg 19.9% Citric acid 2 mg  0.2%

[0191] Formulation R Component Weight % weight Paclitaxel 6 mg 0.6%PEG-20 glyceryl monooleate 500 mg 49.6%  Ethanol 400 mg 39.7% Polysorbate 80 100 mg 9.9% Citric acid 2 mg 0.2%

[0192] Formulation S Component Weight % weight Paclitaxel 6 mg 0.6%PEG-20 glyceryl monooleate 600 mg 59.5%  Ethanol 400 mg 39.7%  Citricacid 2 mg 0.2%

[0193] Formulation T Component Weight % weight Paclitaxel 6 mg 0.6%PEG-20 glyceryl monooleate 550 mg 54.5%  Ethanol 450 mg 44.6%  Citricacid 2 mg 0.2%

[0194] Formulation U Component Weight % weight Paclitaxel 6 mg 0.6%PEG-20 glyceryl monooleate 500 mg 49.6%  Ethanol 500 mg 49.6%  Citricacid 2 mg 0.2%

[0195] Formulation V Component Weight % weight Paclitaxel 6 mg  0.6%Polyethylene Glycol 400 294 mg 29.2% Polysorbate 80 529 mg 52.5% Ethanol176 mg 17.5% Citric Acid 2 mg  0.2%

[0196] Formulation W Component Weight % weight Paclitaxel 6 mg  0.6%Polyethylene Glycol 400 294 mg 29.2% Polysorbate 80 485 mg 48.1% Ethanol221 mg 21.9% Citric Acid 2 mg  0.2%

Example 3

[0197] Animal pK Study of Paclitaxel Formulations:

[0198] Two formulations of the present invention with the followingcompositions were prepared and used for PK studies in rats:

[0199] Sample V (Formulation V): 6 mg/mL paclitaxel dissolved in 29.4%Polyethylene Glycol 400, 52.9% Polysorbate 80, 17.6% Ethanol and 2.0mg/nL citric acid.

[0200] Sample W (Formulation W): 6 mg/mL paclitaxel dissolved in 29.4%Polyethylene Glycol 400, 48.5% Polysorbate 80, 22.1% Ethanol and 2.0mg/mL citric acid.

[0201] Both samples and the control (commercially available Taxol®) werediluted into sterile saline to a final concentration of 1 mg/mL beforedosing. Six male Sprague-Dawley rats (7 weeks old, averaged 270 g each)from Charles River Japan were used per experimental group. Two singleintravenous bolus doses (5 mg/kg and 10 mg/kg) were evaluated at aninfusion rate of 1.5 mL/min. Plasma samples were collected at 0.083,0.5, 1.0, 2.0, 3.0, 4.0, 8.0, and 24.0 hours post-dosing and stored at−20° C. until assayed with HPLC.

[0202] The pK profiles for each of the samples and the control wereprepared, and are illustrated in FIGS. 1-4.

[0203] The results indicate that Samples V and W have very similar PKprofiles in rats. The two formulations have lower AUC compared to thecontrol, presumably due to the well-established non-linearpharmacokinetic interactions between paclitaxel and CREMOPHOR®.

[0204] All of the rats died in the control group (Taxol®) at 10 mg/kgdose. In comparison, all of the animals dosed with formulations V and Wtolerated them well, even at the high dose of 10 mg/kg. These resultssuggest that Formulations V and W have improved safety in rats comparedto TAXOL®.

[0205] The foregoing has demonstrated the pertinent and importantfeatures of the present invention. One of skill in the art will beappreciate that numerous modifications and embodiments may be devised.Therefore, it is intended that the appended claims cover all suchmodifications and embodiments.

What is claimed is:
 1. A pharmaceutical formulation for administrationto a mammal comprising: (a) paclitaxel, a derivative, or apharmaceutically acceptable salt thereof; and (b) one or more of aPEG-glyceryl fatty ester, a quaternary ammonium salt or a PEG-fattyalcohol.
 2. The pharmaceutical formulation of claim 1, wherein theformulation is cremophor free.
 3. The pharmaceutical formulation ofclaim 1, further comprising an additional active.
 4. The pharmaceuticalformulation of claim 3, wherein the additional active is cisplatin,carboplatin, tamoxifen, epirubicin, leuprolide, bicalutamide, goserelinimplant, irinotecan, gemeitabine, or sargramostim or a pharmaceuticallyacceptable salt thereof.
 5. The pharmaceutical formulation of claim 1,wherein the formulation is suitable for dissolution in an aqueousmedium.
 6. The pharmaceutical formulation of claim 1, wherein theformulation is in a form of a solid, semisolid, gel, suspension, oremulsion.
 7. The pharmaceutical formulation of claim 1, wherein theformulation is in liquid form.
 8. The pharmaceutical formulation ofclaim 1, wherein the formulation is in liquid-concentrate form.
 9. Thepharmaceutical formulation of claim 8, further comprising ethanol. 10.The pharmaceutical formulation of claim 6, wherein the solid is alyophilized solid.
 11. The pharmaceutical formulation of claim 1,further comprising an aqueous medium.
 12. The pharmaceutical formulationof claim 11, wherein the formulation is suitable for parenteraladministration.
 13. The pharmaceutical formulation of claim 1, whereinthe formulation is sterile.
 14. The pharmaceutical formulation of claim1, wherein the formulation is in single-unit-dosage form.
 15. Thepharmaceutical formulation of claim 1, wherein the formulation is inmulti-unit-dosage form.
 16. The pharmaceutical formulation of claim 1,further comprising additional excipients.
 17. The pharmaceuticalformulation of claim 1, wherein the quaternary ammonium salt isbenzalkonium chloride, benzethonium chloride, or cetrimide; thePEG-glyceryl fatty ester is PEG-glyceryl monooleate or PEG-glycerylmonolaurate; and the PEG-fatty alcohol is an octoxynol, an oleth, or alaureth.
 18. The pharmaceutical formulation of claim 17, wherein theoctoxynol is octoxynol-9 and the laureth is laureth-23.
 19. Thepharmaceutical formulation of claim 1, wherein per unit weight of thepaclitaxel, the derivative, or the pharmaceutically acceptable saltthereof, a unit weight of the PEG-fatty alcohol or the PEG-glycerylfatty ester ranges from about 5 to about
 200. 20. The pharmaceuticalformulation of claim 1, wherein per unit weight of the paclitaxel, thederivative, or the pharmaceutically acceptable salt thereof, a unitweight of the quaternary ammonium salt ranges from about 0.01 toabout
 1. 21. The pharmaceutical formulation of claim 8, wherein aconcentration of the PEG-fatty alcohol or the PEG-glyceryl fatty esterranges from about 20 weight % to about 99 weight %.
 22. Thepharmaceutical formulation of claim 11, wherein a concentration of thePEG-fatty alcohol or the PEG-glyceryl fatty ester ranges from about 3mg/ml to about 120 mg/ml.
 23. The pharmaceutical formulation of claim11, wherein a concentration of the quaternary ammonium salt ranges fromabout 0.0048 mg/ml to about 0.35 mg/ml.
 24. A pharmaceutical formulationfor administration to a mammal comprising: (a) paclitaxel, a derivative,or a pharmaceutically acceptable salt thereof; and (b) two or more of aPEG-vitamin E, a quaternary ammonium salt, a PEG-monoacid fatty ester, aPEG-glyceryl fatty ester, a polysorbate, or a PEG-fatty alcohol.
 25. Thepharmaceutical formulation of claim 24, wherein the formulation iscremophor free.
 26. The pharmaceutical formulation of claim 24,comprising the PEG-vitamin E and one or more of the PEG-monoacid fattyester, the PEG-glyceryl fatty ester, the polysorbate, or the PEG-fattyalcohol.
 27. The pharmaceutical formulation of claim 24, comprising thequaternary ammonium salt and one or both of the polysorbate or thePEG-fatty alcohol.
 28. The pharmaceutical formulation of claim 24,comprising the PEG-monoacid fatty ester and one or more of thePEG-vitamin E, the PEG-glyceryl fatty ester, the polysorbate, or thePEG-fatty alcohol.
 29. The pharmaceutical formulation of claim 24,comprising the PEG-glyceryl fatty ester and one or more of thePEG-vitamin E, the PEG-monoacid fatty ester, or the polysorbate.
 30. Thepharmaceutical formulation of claim 24, comprising the polysorbate andone or more of the quaternary ammonium salt, the PEG-monoacid fattyester, the PEG-glyceryl fatty ester, or the PEG-fatty alcohol.
 31. Thepharmaceutical formulation of claim 24, comprising the PEG-fatty alcoholand one or more of the PEG-vitamin E, the quaternary ammonium salt, thePEG-monoacid fatty ester, or the polysorbate.
 32. The pharmaceuticalformulation of claim 24, further comprising an additional active. 33.The pharmaceutical formulation of claim 32, wherein the additionalactive is cisplatin, carboplatin, tamoxifen, epirubicin, leuprolide,bicalutamide, goserelin implant, irinotecan, gemcitabine, orsargramostim or a pharmaceutically acceptable salt thereof.
 34. Thepharmaceutical formulation of claim 24, wherein the formulation issuitable for dissolution in an aqueous medium.
 35. The pharmaceuticalformulation of claim 24, wherein the formulation is in a form of asolid, semisolid, gel, suspension, or emulsion.
 36. The pharmaceuticalformulation of claim 24, wherein the formulation is in liquid form. 37.The pharmaceutical formulation of claim 24, wherein the formulation isin liquid-concentrate form.
 38. The pharmaceutical formulation of claim37, further comprising ethanol.
 39. The pharmaceutical formulation ofclaim 35, wherein the solid is a lyophilized solid.
 40. Thepharmaceutical formulation of claim 24, further comprising an aqueousmedium.
 41. The pharmaceutical formulation of claim 40, wherein theformulation is suitable for parenteral administration.
 42. Thepharmaceutical formulation of claim 24, wherein the formulation issterile.
 43. The pharmaceutical formulation of claim 24, wherein theformulation is in single-unit-dosage form.
 44. The pharmaceuticalformulation of claim 24, wherein the formulation is in multi-unit-dosageform.
 45. The pharmaceutical formulation of claim 24, further comprisingadditional excipients.
 46. The pharmaceutical formulation of claim 24,wherein: the PEG-vitamin E is tocophersolan; the quaternary ammoniumsalt is benzalkonium chloride, benzethonium chloride, or cetrimide; thePEG-monoacid fatty ester is PEG-20 monooleate, PEG-20 monolaurate, orPEG-20 monostearate; the PEG-glyceryl fatty ester is PEG-20 glycerylmonooleate, PEG-20 glyceryl monostearate, or PEG-20 glycerylmonolaurate; the polysorbate is polysorbate 20 or polysorbate 80; andthe PEG-fatty alcohol is an octoxynol, an oleth, or a laureth.
 47. Thepharmaceutical formulation of claim 46, wherein the octoxynol isoctoxynol-9 and the laureth is laureth-23.
 48. The pharmaceuticalformulation of claim 24, wherein per unit weight of the paclitaxel, thederivative, or the pharmaceutically acceptable salt thereof, a unitweight of the PEG-vitamin E, the PEG-monoacid fatty ester, thePEG-glyceryl fatty ester, the polysorbate, or the PEG-fatty alcoholranges from about 5 to about
 200. 49. The pharmaceutical formulation ofclaim 24, wherein per unit weight of the paclitaxel, the derivative, orthe pharmaceutically acceptable salt thereof, a unit weight of thequaternary ammonium salt ranges from about 0.01 to about
 1. 50. Thepharmaceutical formulation of claim 40, wherein a concentration of thePEG-vitamin E, the PEG-monoacid fatty ester, the PEG-glyceryl fattyester, the polysorbate, or the PEG-fatty alcohol ranges from about 3mg/ml to about 120 mg/ml.
 51. The pharmaceutical formulation of claim40, wherein a concentration of the quaternary ammonium salt ranges fromabout 0.0048 mg/ml to about 0.35 mg/ml.
 52. The pharmaceuticalformulation of claim 37, wherein a total concentration of the two ormore of the PEG-vitamin E, the PEG-monoacid fatty ester, thePEG-glyceryl fatty ester, the polysorbate, or the PEG-fatty alcoholranges from about 20 weight % to about 99 weight %.
 53. A pharmaceuticalformulation for administration to a mammal comprising: (a) paclitaxel, aderivative, or a pharmaceutically acceptable salt thereof; and (b)PEG-400 and one or more of a PEG-vitamin E, a quaternary ammonium salt,a PEG-monoacid fatty ester, a PEG-glyceryl fatty ester, a polysorbate,or a PEG-fatty alcohol.
 54. The pharmaceutical formulation of claim 53,wherein the formulation is cremophor free.
 55. The pharmaceuticalformulation of claim 53, further comprising an additional active. 56.The pharmaceutical formulation of claim 55, wherein the additionalactive is cisplatin, carboplatin, tamoxifen, epirubicin, leuprolide,bicalutamide, goserelin implant, irinotecan, gemcitabine, orsargramostim or a pharmaceutically acceptable salt thereof.
 57. Thepharmaceutical formulation of claim 53, wherein the formulation issuitable for dissolution in an aqueous medium.
 58. The pharmaceuticalformulation of claim 53, wherein the formulation is in a form of asolid, semisolid, gel, suspension, or emulsion.
 59. The pharmaceuticalformulation of claim 53, wherein the formulation is in liquid form. 60.The pharmaceutical formulation of claim 53, wherein the formulation isin liquid-concentrate form.
 61. The pharmaceutical formulation of claim60, further comprising ethanol.
 62. The pharmaceutical formulation ofclaim 58, wherein the solid is a lyophilized solid.
 63. Thepharmaceutical formulation of claim 53, further comprising an aqueousmedium.
 64. The pharmaceutical formulation of claim 63, wherein theformulation is suitable for parenteral administration.
 65. Thepharmaceutical formulation of claim 53, wherein the formulation issterile.
 66. The pharmaceutical formulation of claim 53, wherein theformulation is in single-unit-dosage form.
 67. The pharmaceuticalformulation of claim 53, wherein the formulation is in multi-unit-dosageform.
 68. The pharmaceutical formulation of claim 53, further comprisingadditional excipients.
 69. The pharmaceutical formulation of claim 53,wherein: the PEG-vitamin E is tocophersolan; the quaternary ammoniumsalt is benzalkonium chloride, benzethonium chloride, or cetrimide; thePEG-monoacid fatty ester is PEG-20 monooleate, PEG-20 monolaurate, orPEG-20 monostearate; the PEG-glyceryl fatty ester is PEG-20 glycerylmonooleate, PEG-20 glyceryl monostearate, or PEG-20 glycerylmonolaurate; the polysorbate is polysorbate 20 or polysorbate 80; andthe PEG-fatty alcohol is an octoxynol, an oleth, or a laureth.
 70. Thepharmaceutical formulation of claim 69, wherein the octoxynol isoctoxynol-9 and the laureth is laureth-23.
 71. A method of treatingcancer in a mammal comprising administering to said mammal atherapeutically effective amount of pharmaceutical formulationcomprising: (a) paclitaxel, a derivative, or a pharmaceuticallyacceptable salt thereof; and (b) one or more of a PEG-glyceryl fattyester, quaternary ammonium salt, or a PEG-fatty alcohol.
 72. The methodof claim 71, wherein the pharmaceutical formulation is cremophor free.73. The method of claim 71, wherein the pharmaceutical formulationcomprises an additional active.
 74. The method of claim 73, wherein theadditional active is cisplatin, carboplatin, tamoxifen, epirubicin,leuprolide, bicalutamide, goserelin implant, irinotecan, gemeitabine, orsargramostim or a pharmaceutically acceptable salt thereof.
 75. Themethod of claim 71, wherein the formulation is suitable for dissolutionin an aqueous medium.
 76. The method of claim 71, wherein formulation isin a form of a solid, semisolid, gel, suspension, or emulsion.
 77. Themethod of claim 71, wherein the formulation is in liquid form.
 78. Themethod of claim 71, wherein the formulation is in liquid-concentrateform.
 79. The method of claim 78, wherein the formulation comprisesethanol.
 80. The method of claim 76, wherein the solid is a lyophilizedsolid.
 81. The method of claim 71, wherein the formulation comprises anaqueous medium.
 82. The method of claim 81, wherein the formulation isadministered parenterally.
 83. The method of claim 71, wherein theformulation is in single-unit-dosage form.
 84. The method of claim 71,wherein the formulation is in multi-unit-dosage form.
 85. The method ofclaim 71, wherein the mammal is a human.
 86. The method of claim71,wherein the formulation is in sterile form.
 87. The method of claim71, wherein the formulation comprises additional excipients.
 88. Themethod of claim 71, wherein the quaternary ammonium salt is benzalkoniumchloride, benzethonium chloride, or cetrimide; the PEG-glyceryl fattyester is PEG-glyceryl monooleate or PEG-glyceryl monolaurate; and thePEG-fatty alcohol is an octoxynol, an oleth, or a laureth.
 89. Themethod of claim 88, wherein the octoxynol is octoxynol-9 and the laurethis laureth-23.
 90. The method of claim 71, wherein per unit weight ofthe paclitaxel, the derivative, or the pharmaceutically acceptable saltthereof, a unit weight of the PEG-fatty alcohol or the PEG-glycerylfatty ester ranges from about 5 to about
 200. 91. The method of claim71, wherein per unit weight of the paclitaxel, the derivative, or thepharmaceutically acceptable salt thereof, a unit weight of thequaternary ammonium salt ranges from about 0.01 to about
 1. 92. Themethod of claim 81, wherein a concentration of the PEG-fatty alcohol andthe PEG-glyceryl fatty ester ranges from about 3 mg/ml to about 120mg/ml.
 93. The method of claim 81, wherein a concentration of thequaternary ammonium salt ranges from about 0.0048 mg/ml to about 0.35mg/ml.
 94. The method of claim 78, wherein a concentration of thePEG-fatty alcohol or the PEG-glyceryl fatty ester ranges from about 20weight % to about 99 weight %.
 95. A method of treating cancer in amammal comprising administering to said mammal a therapeuticallyeffective amount of a pharmaceutical formulation comprising: (a)paclitaxel, a derivative, or a pharmaceutically acceptable salt thereof;and (b) two or more of a PEG-vitamin E, a quaternary ammonium salt, aPEG-monoacid fatty ester, a polysorbate, or a PEG-fatty alcohol.
 96. Themethod of claim 95, wherein the pharmaceutical formulation is cremophorfree.
 97. The method of claim 95, the pharmaceutical formulationcomprising the PEG-vitamin E and one or more of the PEG-monoacid fattyester, the PEG-glyceryl fatty ester, the polysorbate, or the PEG-fattyalcohol.
 98. The method of claim 95, the pharmaceutical formulationcomprising the quaternary ammonium salt and one or both of thepolysorbate or the PEG-fatty alcohol.
 99. The method of claim 95, thepharmaceutical formulation comprising the PEG-monoacid fatty ester andone or more of the PEG-vitamin E, the PEG-glyceryl fatty ester, thepolysorbate, or the PEG-fatty alcohol.
 100. The method of claim 95, thepharmaceutical formulation comprising the PEG-glyceryl fatty ester andone or more of the PEG-vitamin E, the PEG-monoacid fatty ester, or thepolysorbate.
 101. The method of claim 95, the pharmaceutical formulationcomprising the polysorbate and one or more of the quaternary ammoniumsalt, the PEG-monoacid fatty ester, the PEG-glyceryl fatty ester, or thePEG-fatty alcohol.
 102. The method of claim 95, the pharmaceuticalformulation comprising the PEG-fatty alcohol and one or more of thePEG-vitamin E, the quaternary ammonium salt, the PEG-monoacid fattyester, or the polysorbate.
 103. The method of claim 95, wherein theformulation comprises an additional active.
 104. The method of claim103, wherein the additional active is cisplatin, carboplatin, tamoxifen,epirubicin, leuprolide, bicalutamide, goserelin implant, irinotecan,gemcitabine, or sargramostim or a pharmaceutically acceptable saltthereof.
 105. The method of claim 95, wherein the formulation issuitable for dissolution in an aqueous medium.
 106. The method of claim95, wherein the formulation is in a form of a solid, semisolid, gel,suspension, or emulsion.
 107. The method of claim 95, wherein theformulation is in liquid form.
 108. The method of claim 95, wherein theformulation is in liquid-concentrate form.
 109. The method of claim 108,wherein the formulation comprises ethanol.
 110. The method of claim 106,wherein the solid is a lyophilized solid.
 111. The method of claim 95,wherein the formulation comprises an aqueous medium.
 112. The method ofclaim 111, wherein the formulation is administered parenterally. 113.The method of claim 95, wherein the formulation is in single-unit-dosageform.
 114. The method of claim 95, wherein the formulation is inmulti-unit-dosage form.
 115. The method of claim 95, wherein the mammalis a human.
 116. The method of claim 95, wherein the formulation is insterile form.
 117. The method of claim 95, wherein the formulationcomprises additional excipients.
 118. The method of claim 95, wherein:the PEG-vitamin E is tocophersolan; the quaternary ammonium salt isbenzalkonium chloride, benzethonium chloride, or cetrimide; thePEG-monoacid fatty ester is PEG-20 monooleate, PEG-20 monolaurate,PEG-20 monostearate; the PEG-glyceryl fatty ester is PEG-20 glycerylmonooleate, PEG-20 glyceryl monostearate, or PEG-20 glyceryl monolauratethe polysorbate is polysorbate 20 or polysorbate 80; and the PEG-fattyalcohol is an octoxynol, an oleth, or a laureth.
 119. The method ofclaim 118, wherein the octoxynol is octoxynol-9 and the laureth islaureth-23.
 120. The method of claim 95, wherein per unit weight of thepaclitaxel, the derivative, or the pharmaceutically acceptable saltthereof, a unit weight of the PEG-vitamin E, the PEG-monoacid fattyester, the PEG-glyceryl fatty ester, the polysorbate, or the PEG-fattyalcohol ranges from about 5 to about
 200. 121. The method of claim 95,wherein per unit weight of the paclitaxel, the derivative, or thepharmaceutically acceptable salt thereof, a unit weight of thequaternary ammonium salt ranges from about 0.01 to about
 1. 122. Themethod of claim 111, wherein a concentration of the PEG-vitamin E, thePEG-monoacid fatty ester, the PEG-glyceryl fatty ester, the polysorbate,or the PEG-fatty alcohol ranges from about 3 mg/ml to about 120 mg/ml.123. The method of claim 111, wherein a concentration of the quaternaryammonium salt ranges from about 0.0048 mg/mil to about 0.35 mg/ml. 124.The method of claim 108, wherein a total concentration of the two ormore of the PEG-vitamin E, the PEG-monoacid fatty ester, thePEG-glyceryl fatty ester, the polysorbate, or the PEG-fatty alcoholranges from about 20 weight % to about 99 weight %.
 125. Apharmaceutical formulation suitable for administration to a humanconsisting essentially of: (a) paclitaxel, a derivative, or apharmaceutically acceptable salt thereof; (b) one or more of aPEG-vitamin E, a quaternary ammonium salt, a PEG-monoacid fatty ester, aPEG-glyceryl fatty ester, a polysorbate, or a PEG-fatty alcohol; and (c)ethanol, wherein said formulation is free of cremophor and is suitablefor dissolution or reconstitution with an aqueous medium into aparticulate-free solution suitable for parenteral administration. 126.The pharmaceutical formulation of claim 125, wherein: the PEG-vitamin Eis tocophersolan; the quaternary ammonium salt is benzalkonium chloride,benzethonium chloride, or cetrimide; the PEG-monoacid fatty ester isPEG-20 monooleate, PEG-20 monolaurate, PEG-20 monostearate; thePEG-glyceryl fatty ester is PEG-20 glyceryl monooleate, PEG-20 glycerylmonostearate, or PEG-20 glyceryl monolaurate; the polysorbate ispolysorbate 20 or polysorbate 80; and the PEG-fatty alcohol is anoctoxynol, an oleth, or a laureth.
 127. The pharmaceutical formulationof claim 126, wherein the octoxynol is octoxynol-9 and the laureth islaureth-23.
 128. The pharmaceutical formulation of claim 125, whereinthe formulation is sterile.
 129. The pharmaceutical formulation of claim125, wherein the formulation is in single-unit-dosage form.
 130. Thepharmaceutical formulation of claim 125, wherein the formulation is inmulti-unit-dosage form.
 131. A pharmaceutical formulation suitable foradministration to a human consisting essentially of: (a) paclitaxel, aderivative, or a pharmaceutically acceptable salt thereof; (b) two ormore of a PEG-vitamin E, a quaternary ammonium salt, a PEG-monoacidfatty ester, a PEG-glyceryl fatty ester; a polysorbate, or a PEG-fattyalcohol; and (c) ethanol, wherein said formulation is free of cremophorand is suitable for dissolution or reconstitution with an aqueous mediuminto a particulate-free solution suitable for parenteral administration.132. The pharmaceutical formulation of claim 131, wherein: thePEG-vitamin E is tocophersolan; the quaternary ammonium salt isbenzalkonium chloride, benzethonium chloride, or cetrimide; thePEG-monoacid fatty ester is PEG-20 monooleate, PEG-20 monolaurate,PEG-20 monostearate; the PEG-glyceryl fatty ester is PEG-20 glycerylmonooleate, PEG-20 glyceryl monostearate, or PEG-20 glycerylmonolaurate; the polysorbate is polysorbate 20 or polysorbate 80; andthe PEG-fatty alcohol is an octoxynol, an oleth, or a laureth.
 133. Thepharmaceutical formulation of claim 132, wherein the octoxynol isoctoxynol-9 and the laureth is laureth-23.
 134. The pharmaceuticalformulation of claim 131, comprising the PEG-vitamin E and one or moreof the PEG-monoacid fatty ester, the PEG-glyceryl fatty ester, thepolysorbate, or the PEG-fatty alcohol.
 135. The pharmaceuticalformulation of claim 131, comprising the quaternary ammonium salt andone or both of the polysorbate or the PEG-fatty alcohol.
 136. Thepharmaceutical formulation of claim 131, comprising the PEG-monoacidfatty ester and one or more of the PEG-vitamin E, the PEG-glyceryl fattyester, the polysorbate, or the PEG-fatty alcohol.
 137. Thepharmaceutical formulation of claim 131, comprising the polysorbate andone or more of the quaternary ammonium salt, the PEG-monoacid fattyester, the PEG-glyceryl fatty ester, or the PEG-fatty alcohol.
 138. Thepharmaceutical formulation of claim 131, comprising the PEG-fattyalcohol and one or more of the PEG-monoacid fatty ester, thePEG-monoacid fatty ester, or the polysorbate.
 139. The pharmaceuticalformulation of claim 131, wherein the formulation is sterile.
 140. Thepharmaceutical formulation of claim 131, wherein the formulation is insingle-unit-dosage form.
 141. The pharmaceutical formulation of claim131, wherein the formulation is in multi-unit-dosage form.
 142. Thepharmaceutical formulation of claim 131, further comprising additionalexcipients.
 143. An array of samples, each sample comprising paclitaxel,a derivative, or a pharmaceutically acceptable salt thereof and one ormore formulation components, wherein each sample differs from any othersample with respect to at least one of: (i) the identity of theformulation component, or (ii) the ratio of the paclitaxel, thederivative, or the pharmaceutically acceptable salt thereof to theformulation component.
 144. The array of claim 143, of at least 24samples.
 145. The array of claim 143, of at least 48 samples.
 146. Thearray of claim 143, of at least 96 samples.
 147. A method to find apharmaceutical formulation suitable to administer paclitaxel, aderivative, or a pharmaceutically acceptable salt thereof to a mammal,comprising: (a) preparing an array of samples, each sample comprisingthe paclitaxel, the derivative, or the pharmaceutically acceptable saltthereof and one or more formulation components, wherein each samplediffers from any other sample with respect to at least one of: (i) theidentity of the formulation component, (ii) the ratio of the paclitaxel,the derivative, or the pharmaceutically acceptable salt thereof to theformulation component; and (b) testing each sample for a property. 148.The method of claim 147, wherein the property is solubility.
 149. Themethod of claim 147, wherein the array comprises at least 24 samples.150. The method of claim 147, wherein the array comprises at least 48samples.
 151. The method of claim 147, wherein the array comprises atleast 96 samples.
 152. The method of claim 147, wherein at least 1000samples are tested per day.
 153. A particulate-free pharmaceuticalformulation suitable for parenteral administration to a mammalcomprising about 0.2 mg/ml to about 3 mg/ml of paclitaxel in anon-cremophor aqueous-based solution, where per mg of the paclitaxel inthe formulation the amount of water is about 4.5 ml to about 0.3 ml.